TBD Meeting (4154-19)

BARCELONA – Further differences in how adults and adolescents with type 2 diabetes respond to glucose and glucagon have been demonstrated by new data from the Restoring Insulin SEcretion (RISE) studies presented at the annual meeting of the European Association for the Study of Diabetes.

In a comparison of responses to an oral glucose tolerance test (OGTT), youth (n = 85) were more likely than were adults (n = 353) to have a biphasic type of glucose response curve (18.8% vs. 8.2%, respectively), which is considered a more normal response curve. However, that “did not foretell an advantageous outcome to the RISE interventions in the younger age group,” said study investigator Silva Arslanian, MD, of UPMC Children’s Hospital of Pittsburgh.

Fewer youth than adults had an incessant response (10.6% vs. 14.5%, respectively) or monophasic response to an OGTT (70.6% vs. 77.3%), and that was associated with lower beta-cell responses, compared with individuals with monophasic or biphasic glucose curves.

“Irrespective of curve type, insulin sensitivity was lower in youth than in adults,” Dr. Arslanian said. She added that beta-cell responses were greater in youth than in adults, except in youth with the worst incessant-increase curve type. In youth with the incessant-increase glucose curve, there was no evidence of beta-cell hypersecretion, which suggested youth “have more severe beta-cell dysfunction,” compared with adults.

There were also data presented on whether differences in alpha-cell function between youth and adults might be important. Those data showed that although fasting glucagon concentrations did not increase with fasting glucose in youth, they did in adults. It was found that fasting and stimulated glucagon concentrations were lower in youth than in adults, meaning that “alpha-cell function does not explain the beta-cell hyperresponsiveness seen in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes,” reported study investigator Steven Kahn, MD, ChB, of VA Puget Sound Health Care System, University of Washington, Seattle.

M. Alexander Otto/MDedge News

“What was new, however, was that [the beta-cells of] youth were hyperresponsive and were really making large amounts of insulin.” Increased insulin production might be expected when there is insulin resistance, he added, but the level seen was “more than you would expect.” Over time, that might be toxic to the beta cells, and evidence from the earlier TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) studies suggested that the rate of beta-cell dysfunction was more rapid in youth than in adults.

Giving his perspective, as a pediatrician, on the new OGTT analyses from the RISE studies, Dr. Zeitler said that these data showed that the characteristic beta-cell hyperresponsiveness seen in youth “actually disappears as glycemia worsens.” In youth with the incessant glucose response pattern, “it shows that they cannot tolerate glucose, and their glucose levels just go up and up and up” until the beta cells fail.

This is a critical observation, Dr. Zeitler said, noting that it “sort of had to be the case, because sooner or later you had to lose beta cells ... this is probably the point where aggressive therapy is needed ... it was always a bit of a paradox, if these kids have such an aggressive course, how come they were starting out being so hyperresponsive?”

With regard to alpha-cell function, “these are really fresh data. We haven’t really had a long time to think about it,” said Dr. Zeitler. “What I find interesting is that there isn’t alpha-cell glucagon hypersecretion in youth like there is in adults.” That may be because youth are making so much insulin that they are suppressing glucagon production, but that’s not an entirely satisfying answer,” he said.

“The TODAY study demonstrated that diabetes in kids is aggressive; these RISE data now start to put some physiology around that, why is it more aggressive? Hyperresponsiveness, loss of beta-cell function over time, lack of response to intervention, compared with the adults.”

As for the clinical implications, Dr. Zeitler said that this is further evidence that the default approach to treating younger patients with greater caution than adults is perhaps not the best way to treat type 2 diabetes.

“These data are really showing that there is a very important toxic period that is occurring in these kids early on [and] that probably argues for more, not less, aggressive therapy,” than with adults. “Clearly, something is happening that is putting them at really big risk for rapid progression, and that’s your chance to treat much more aggressively, much earlier.”

The RISE studies are sponsored by the RISE Study Group in collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Zeitler disclosed that he had acted as a consultant to Boehringer-Ingelheim, Eli Lilly, Daiichi-Sankyo and Merck, Sharp & Dohme, and had received research support from Janssen. Dr. Arslanian stated that she has nothing to disclose. Dr. Khan did not provide any disclosure information.

SOURCES: Arslanian S. EASD 2019, Oral presentation S34.1; Kahn S. EASD 2019, Oral presentation S34.3

BARCELONA – Further differences in how adults and adolescents with type 2 diabetes respond to glucose and glucagon have been demonstrated by new data from the Restoring Insulin SEcretion (RISE) studies presented at the annual meeting of the European Association for the Study of Diabetes.

In a comparison of responses to an oral glucose tolerance test (OGTT), youth (n = 85) were more likely than were adults (n = 353) to have a biphasic type of glucose response curve (18.8% vs. 8.2%, respectively), which is considered a more normal response curve. However, that “did not foretell an advantageous outcome to the RISE interventions in the younger age group,” said study investigator Silva Arslanian, MD, of UPMC Children’s Hospital of Pittsburgh.

Fewer youth than adults had an incessant response (10.6% vs. 14.5%, respectively) or monophasic response to an OGTT (70.6% vs. 77.3%), and that was associated with lower beta-cell responses, compared with individuals with monophasic or biphasic glucose curves.

“Irrespective of curve type, insulin sensitivity was lower in youth than in adults,” Dr. Arslanian said. She added that beta-cell responses were greater in youth than in adults, except in youth with the worst incessant-increase curve type. In youth with the incessant-increase glucose curve, there was no evidence of beta-cell hypersecretion, which suggested youth “have more severe beta-cell dysfunction,” compared with adults.

There were also data presented on whether differences in alpha-cell function between youth and adults might be important. Those data showed that although fasting glucagon concentrations did not increase with fasting glucose in youth, they did in adults. It was found that fasting and stimulated glucagon concentrations were lower in youth than in adults, meaning that “alpha-cell function does not explain the beta-cell hyperresponsiveness seen in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes,” reported study investigator Steven Kahn, MD, ChB, of VA Puget Sound Health Care System, University of Washington, Seattle.

M. Alexander Otto/MDedge News

“What was new, however, was that [the beta-cells of] youth were hyperresponsive and were really making large amounts of insulin.” Increased insulin production might be expected when there is insulin resistance, he added, but the level seen was “more than you would expect.” Over time, that might be toxic to the beta cells, and evidence from the earlier TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) studies suggested that the rate of beta-cell dysfunction was more rapid in youth than in adults.

Giving his perspective, as a pediatrician, on the new OGTT analyses from the RISE studies, Dr. Zeitler said that these data showed that the characteristic beta-cell hyperresponsiveness seen in youth “actually disappears as glycemia worsens.” In youth with the incessant glucose response pattern, “it shows that they cannot tolerate glucose, and their glucose levels just go up and up and up” until the beta cells fail.

This is a critical observation, Dr. Zeitler said, noting that it “sort of had to be the case, because sooner or later you had to lose beta cells ... this is probably the point where aggressive therapy is needed ... it was always a bit of a paradox, if these kids have such an aggressive course, how come they were starting out being so hyperresponsive?”

With regard to alpha-cell function, “these are really fresh data. We haven’t really had a long time to think about it,” said Dr. Zeitler. “What I find interesting is that there isn’t alpha-cell glucagon hypersecretion in youth like there is in adults.” That may be because youth are making so much insulin that they are suppressing glucagon production, but that’s not an entirely satisfying answer,” he said.

“The TODAY study demonstrated that diabetes in kids is aggressive; these RISE data now start to put some physiology around that, why is it more aggressive? Hyperresponsiveness, loss of beta-cell function over time, lack of response to intervention, compared with the adults.”

As for the clinical implications, Dr. Zeitler said that this is further evidence that the default approach to treating younger patients with greater caution than adults is perhaps not the best way to treat type 2 diabetes.

“These data are really showing that there is a very important toxic period that is occurring in these kids early on [and] that probably argues for more, not less, aggressive therapy,” than with adults. “Clearly, something is happening that is putting them at really big risk for rapid progression, and that’s your chance to treat much more aggressively, much earlier.”

The RISE studies are sponsored by the RISE Study Group in collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Zeitler disclosed that he had acted as a consultant to Boehringer-Ingelheim, Eli Lilly, Daiichi-Sankyo and Merck, Sharp & Dohme, and had received research support from Janssen. Dr. Arslanian stated that she has nothing to disclose. Dr. Khan did not provide any disclosure information.

SOURCES: Arslanian S. EASD 2019, Oral presentation S34.1; Kahn S. EASD 2019, Oral presentation S34.3

BARCELONA – Further differences in how adults and adolescents with type 2 diabetes respond to glucose and glucagon have been demonstrated by new data from the Restoring Insulin SEcretion (RISE) studies presented at the annual meeting of the European Association for the Study of Diabetes.

In a comparison of responses to an oral glucose tolerance test (OGTT), youth (n = 85) were more likely than were adults (n = 353) to have a biphasic type of glucose response curve (18.8% vs. 8.2%, respectively), which is considered a more normal response curve. However, that “did not foretell an advantageous outcome to the RISE interventions in the younger age group,” said study investigator Silva Arslanian, MD, of UPMC Children’s Hospital of Pittsburgh.

Fewer youth than adults had an incessant response (10.6% vs. 14.5%, respectively) or monophasic response to an OGTT (70.6% vs. 77.3%), and that was associated with lower beta-cell responses, compared with individuals with monophasic or biphasic glucose curves.

“Irrespective of curve type, insulin sensitivity was lower in youth than in adults,” Dr. Arslanian said. She added that beta-cell responses were greater in youth than in adults, except in youth with the worst incessant-increase curve type. In youth with the incessant-increase glucose curve, there was no evidence of beta-cell hypersecretion, which suggested youth “have more severe beta-cell dysfunction,” compared with adults.

There were also data presented on whether differences in alpha-cell function between youth and adults might be important. Those data showed that although fasting glucagon concentrations did not increase with fasting glucose in youth, they did in adults. It was found that fasting and stimulated glucagon concentrations were lower in youth than in adults, meaning that “alpha-cell function does not explain the beta-cell hyperresponsiveness seen in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes,” reported study investigator Steven Kahn, MD, ChB, of VA Puget Sound Health Care System, University of Washington, Seattle.

M. Alexander Otto/MDedge News

“What was new, however, was that [the beta-cells of] youth were hyperresponsive and were really making large amounts of insulin.” Increased insulin production might be expected when there is insulin resistance, he added, but the level seen was “more than you would expect.” Over time, that might be toxic to the beta cells, and evidence from the earlier TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) studies suggested that the rate of beta-cell dysfunction was more rapid in youth than in adults.

Giving his perspective, as a pediatrician, on the new OGTT analyses from the RISE studies, Dr. Zeitler said that these data showed that the characteristic beta-cell hyperresponsiveness seen in youth “actually disappears as glycemia worsens.” In youth with the incessant glucose response pattern, “it shows that they cannot tolerate glucose, and their glucose levels just go up and up and up” until the beta cells fail.

This is a critical observation, Dr. Zeitler said, noting that it “sort of had to be the case, because sooner or later you had to lose beta cells ... this is probably the point where aggressive therapy is needed ... it was always a bit of a paradox, if these kids have such an aggressive course, how come they were starting out being so hyperresponsive?”

With regard to alpha-cell function, “these are really fresh data. We haven’t really had a long time to think about it,” said Dr. Zeitler. “What I find interesting is that there isn’t alpha-cell glucagon hypersecretion in youth like there is in adults.” That may be because youth are making so much insulin that they are suppressing glucagon production, but that’s not an entirely satisfying answer,” he said.

“The TODAY study demonstrated that diabetes in kids is aggressive; these RISE data now start to put some physiology around that, why is it more aggressive? Hyperresponsiveness, loss of beta-cell function over time, lack of response to intervention, compared with the adults.”

As for the clinical implications, Dr. Zeitler said that this is further evidence that the default approach to treating younger patients with greater caution than adults is perhaps not the best way to treat type 2 diabetes.

“These data are really showing that there is a very important toxic period that is occurring in these kids early on [and] that probably argues for more, not less, aggressive therapy,” than with adults. “Clearly, something is happening that is putting them at really big risk for rapid progression, and that’s your chance to treat much more aggressively, much earlier.”

The RISE studies are sponsored by the RISE Study Group in collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Zeitler disclosed that he had acted as a consultant to Boehringer-Ingelheim, Eli Lilly, Daiichi-Sankyo and Merck, Sharp & Dohme, and had received research support from Janssen. Dr. Arslanian stated that she has nothing to disclose. Dr. Khan did not provide any disclosure information.

SOURCES: Arslanian S. EASD 2019, Oral presentation S34.1; Kahn S. EASD 2019, Oral presentation S34.3

BARCELONA – A similar overall risk of symptomatic hypoglycemia was observed with insulin degludec (Tresiba) and insulin glargine U300 (Toujeo) in the phase 3 CONCLUDE study data presented at the annual meeting of the European Association for the Study of Diabetes.

Sara Freeman/MDedge News

During a 36-week maintenance treatment period, the rate ratio (RR) for the primary endpoint of the study – severe or confirmed symptomatic hypoglycemia, defined as a blood-glucose level of less than 3.1 mmol/L (56 mg/dL) – was 0.88 (95% confidence interval, 0.73-1.06; P = .17) in a comparison the two long-acting insulins.

There were some differences that favored insulin degludec over insulin glargine when other endpoints were considered, but because a statistical testing hierarchy was used, “no confirmatory results can be made from CONCLUDE,” one of the study investigators, Athena Philis-Tsimikas, MD, of Scripps Whittier Diabetes Institute, San Diego, said during a special symposium at the meeting.

“If the primary endpoint was not achieved, the testing hierarchy stopped after the first occurrence of nonsignificance,” she explained. Although that occurred, the other endpoints could still be analyzed as they were all prespecified, she argued. These showed that during the maintenance treatment period, there were lower rates of nocturnal symptomatic hypoglycemic episodes (RR, 0.63; 95% CI, 0.48-0.84; P = .0014) and severe episodes (those requiring third-party assistance; RR, 0.20; 95% CI, 0.07-0.57; P = .0027) with insulin degludec, compared with insulin glargine.

The trial came under fire, however, from Stefano Del Prato, MD, professor of endocrinology in the department of endocrinology metabolism and chief of the section of diabetes at the University of Pisa, Italy, who provided the EASD-invited independent commentary on the study’s findings. “This is the CONCLUDE trial. You’d could expect a CONCLUDE trial to be conclusive in its conclusions!” he said, noting that there were “too many uncertainties” in the trial.

CONCLUDE was a randomized, open-label, head-to-head study of insulin degludec versus insulin glargine in 1,609 adult patients with type 2 diabetes who were inadequately treated with basal insulin with or without oral antidiabetic drugs. The aim of the trial was to evaluate the risk of hypoglycemia associated with the two long-acting insulins.

“Hypoglycemia is a very common event in both type 1 and type 2 diabetes,” Thomas Pieber, MD, Medical University Graz, Austria, reminded the audience. Severe hypoglycemia is associated with insulin use, and data show that patients with type 2 diabetes are at as much risk as are those with type 1 diabetes in the longer term (Diabetologia. 2007;50:1140-7).

Sara Freeman/MDedge News

Sara Freeman/MDedge News

He said that it was not clear from the findings why there might be a lower risk of hypoglycemia with insulin degludec. He noted that the rate of diurnal hypoglycemia should be considered, and that the statistical interpretation of the data may be “a matter of uncertainty as well.”

Dr. Del Prato agreed that “prevention of hypoglycemia remained a major task in treating type 2 diabetic patients, particularly those on insulin therapy.” He proposed that differentiating between new basal insulin analogs may need “better tools for characterization of PK/PD, rigorous interpretation of the results, careful assessment of the generalizability of results from randomized controlled trials performed in selected study populations, and independent research and careful real-world studies to be performed.”

Furthermore, he said translating the potential benefit of new insulin analogs “cannot just rely on their properties, rather it requires validation over the time of the accuracy of glucose meters, and adequate patient education, and even more, education reinforcement.”

All of the speakers disclosed ties with Novo Nordisk, which funded the study, as well as other pharmaceutical companies.
 

SOURCES: Philis-Tsimikas A. EASD 2019, Oral Presentation 90; Pieber T. EASD 2019, Oral Presentation S38.1; Philis-Tsimikas A. EASD 2019, Oral Presentation S38.2; Del Prato S. EASD 2019. Oral Presentation S38.3.

BARCELONA – A similar overall risk of symptomatic hypoglycemia was observed with insulin degludec (Tresiba) and insulin glargine U300 (Toujeo) in the phase 3 CONCLUDE study data presented at the annual meeting of the European Association for the Study of Diabetes.

Sara Freeman/MDedge News

During a 36-week maintenance treatment period, the rate ratio (RR) for the primary endpoint of the study – severe or confirmed symptomatic hypoglycemia, defined as a blood-glucose level of less than 3.1 mmol/L (56 mg/dL) – was 0.88 (95% confidence interval, 0.73-1.06; P = .17) in a comparison the two long-acting insulins.

There were some differences that favored insulin degludec over insulin glargine when other endpoints were considered, but because a statistical testing hierarchy was used, “no confirmatory results can be made from CONCLUDE,” one of the study investigators, Athena Philis-Tsimikas, MD, of Scripps Whittier Diabetes Institute, San Diego, said during a special symposium at the meeting.

“If the primary endpoint was not achieved, the testing hierarchy stopped after the first occurrence of nonsignificance,” she explained. Although that occurred, the other endpoints could still be analyzed as they were all prespecified, she argued. These showed that during the maintenance treatment period, there were lower rates of nocturnal symptomatic hypoglycemic episodes (RR, 0.63; 95% CI, 0.48-0.84; P = .0014) and severe episodes (those requiring third-party assistance; RR, 0.20; 95% CI, 0.07-0.57; P = .0027) with insulin degludec, compared with insulin glargine.

The trial came under fire, however, from Stefano Del Prato, MD, professor of endocrinology in the department of endocrinology metabolism and chief of the section of diabetes at the University of Pisa, Italy, who provided the EASD-invited independent commentary on the study’s findings. “This is the CONCLUDE trial. You’d could expect a CONCLUDE trial to be conclusive in its conclusions!” he said, noting that there were “too many uncertainties” in the trial.

CONCLUDE was a randomized, open-label, head-to-head study of insulin degludec versus insulin glargine in 1,609 adult patients with type 2 diabetes who were inadequately treated with basal insulin with or without oral antidiabetic drugs. The aim of the trial was to evaluate the risk of hypoglycemia associated with the two long-acting insulins.

“Hypoglycemia is a very common event in both type 1 and type 2 diabetes,” Thomas Pieber, MD, Medical University Graz, Austria, reminded the audience. Severe hypoglycemia is associated with insulin use, and data show that patients with type 2 diabetes are at as much risk as are those with type 1 diabetes in the longer term (Diabetologia. 2007;50:1140-7).

Sara Freeman/MDedge News

Sara Freeman/MDedge News

He said that it was not clear from the findings why there might be a lower risk of hypoglycemia with insulin degludec. He noted that the rate of diurnal hypoglycemia should be considered, and that the statistical interpretation of the data may be “a matter of uncertainty as well.”

Dr. Del Prato agreed that “prevention of hypoglycemia remained a major task in treating type 2 diabetic patients, particularly those on insulin therapy.” He proposed that differentiating between new basal insulin analogs may need “better tools for characterization of PK/PD, rigorous interpretation of the results, careful assessment of the generalizability of results from randomized controlled trials performed in selected study populations, and independent research and careful real-world studies to be performed.”

Furthermore, he said translating the potential benefit of new insulin analogs “cannot just rely on their properties, rather it requires validation over the time of the accuracy of glucose meters, and adequate patient education, and even more, education reinforcement.”

All of the speakers disclosed ties with Novo Nordisk, which funded the study, as well as other pharmaceutical companies.
 

SOURCES: Philis-Tsimikas A. EASD 2019, Oral Presentation 90; Pieber T. EASD 2019, Oral Presentation S38.1; Philis-Tsimikas A. EASD 2019, Oral Presentation S38.2; Del Prato S. EASD 2019. Oral Presentation S38.3.

BARCELONA – A similar overall risk of symptomatic hypoglycemia was observed with insulin degludec (Tresiba) and insulin glargine U300 (Toujeo) in the phase 3 CONCLUDE study data presented at the annual meeting of the European Association for the Study of Diabetes.

Sara Freeman/MDedge News

During a 36-week maintenance treatment period, the rate ratio (RR) for the primary endpoint of the study – severe or confirmed symptomatic hypoglycemia, defined as a blood-glucose level of less than 3.1 mmol/L (56 mg/dL) – was 0.88 (95% confidence interval, 0.73-1.06; P = .17) in a comparison the two long-acting insulins.

There were some differences that favored insulin degludec over insulin glargine when other endpoints were considered, but because a statistical testing hierarchy was used, “no confirmatory results can be made from CONCLUDE,” one of the study investigators, Athena Philis-Tsimikas, MD, of Scripps Whittier Diabetes Institute, San Diego, said during a special symposium at the meeting.

“If the primary endpoint was not achieved, the testing hierarchy stopped after the first occurrence of nonsignificance,” she explained. Although that occurred, the other endpoints could still be analyzed as they were all prespecified, she argued. These showed that during the maintenance treatment period, there were lower rates of nocturnal symptomatic hypoglycemic episodes (RR, 0.63; 95% CI, 0.48-0.84; P = .0014) and severe episodes (those requiring third-party assistance; RR, 0.20; 95% CI, 0.07-0.57; P = .0027) with insulin degludec, compared with insulin glargine.

The trial came under fire, however, from Stefano Del Prato, MD, professor of endocrinology in the department of endocrinology metabolism and chief of the section of diabetes at the University of Pisa, Italy, who provided the EASD-invited independent commentary on the study’s findings. “This is the CONCLUDE trial. You’d could expect a CONCLUDE trial to be conclusive in its conclusions!” he said, noting that there were “too many uncertainties” in the trial.

CONCLUDE was a randomized, open-label, head-to-head study of insulin degludec versus insulin glargine in 1,609 adult patients with type 2 diabetes who were inadequately treated with basal insulin with or without oral antidiabetic drugs. The aim of the trial was to evaluate the risk of hypoglycemia associated with the two long-acting insulins.

“Hypoglycemia is a very common event in both type 1 and type 2 diabetes,” Thomas Pieber, MD, Medical University Graz, Austria, reminded the audience. Severe hypoglycemia is associated with insulin use, and data show that patients with type 2 diabetes are at as much risk as are those with type 1 diabetes in the longer term (Diabetologia. 2007;50:1140-7).

Sara Freeman/MDedge News

Sara Freeman/MDedge News

He said that it was not clear from the findings why there might be a lower risk of hypoglycemia with insulin degludec. He noted that the rate of diurnal hypoglycemia should be considered, and that the statistical interpretation of the data may be “a matter of uncertainty as well.”

Dr. Del Prato agreed that “prevention of hypoglycemia remained a major task in treating type 2 diabetic patients, particularly those on insulin therapy.” He proposed that differentiating between new basal insulin analogs may need “better tools for characterization of PK/PD, rigorous interpretation of the results, careful assessment of the generalizability of results from randomized controlled trials performed in selected study populations, and independent research and careful real-world studies to be performed.”

Furthermore, he said translating the potential benefit of new insulin analogs “cannot just rely on their properties, rather it requires validation over the time of the accuracy of glucose meters, and adequate patient education, and even more, education reinforcement.”

All of the speakers disclosed ties with Novo Nordisk, which funded the study, as well as other pharmaceutical companies.
 

SOURCES: Philis-Tsimikas A. EASD 2019, Oral Presentation 90; Pieber T. EASD 2019, Oral Presentation S38.1; Philis-Tsimikas A. EASD 2019, Oral Presentation S38.2; Del Prato S. EASD 2019. Oral Presentation S38.3.

BARCELONA – The glucagonlike peptide–1 receptor antagonist semaglutide (Ozempic) produced greater reductions in glycated hemoglobin and body weight than the sodium-glucose cotransporter 2 inhibitor canagliflozin (Invokana) in second-line treatment in patients with type 2 diabetes after metformin and lifestyle modifications, researchers reported at the annual meeting of the European Association for the Study of Diabetes.

The year-long SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) 8 trial comparing semaglutide and canagliflozin is one of the few head-to-head comparisons of the glucagonlike peptide–1 receptor antagonist (GLP-1 RA) and sodium-glucose cotransporter 2 (SGLT2) inhibitor classes of drugs.

Findings showed overall changes in HbA_{1c level} from baseline to week 52 of –1.5 percentage points with semaglutide and –1.0 percentage point with canagliflozin, and changes in body weight during the same time of –5.3 kg and –4.2 kg, respectively. The estimated treatment differences were –0.49 percentage points for HbA_1c (P less than .001) and –1.06 kg for body weight (P less than .0029).

A significantly higher percentage of patients receiving semaglutide also achieved HbA_1c targets at 52 weeks, compared with those receiving canagliflozin: 66.1% versus 45.1%, respectively, achieved the American Diabetes Association’s target of less than 7%, and 52.8% versus 23.6% (P less than .0001) reached the lower target of 6.5% or lower, as set by the American Association of Clinical Endocrinologists.

Furthermore, a significantly higher proportion of patients in the semaglutide arm achieved 10% or more weight loss by the end of the study (22.3% vs. 8.9% in the canagliflozin arm; P less than .0001), with a trend for 5% or greater weight loss favoring semaglutide (51.1% vs. 46.6%, P = .21). A post hoc analysis also showed that patients treated with semaglutide could achieve a weight loss of 15% or more (6.8% vs. 0.9% for canagliflozin, P = .0001).

“SUSTAIN 8 provides clinically relevant information regarding the head-to-head comparison of these two very commonly used glucose-lowering classes [of drugs] as second-line therapy in patients with type 2 diabetes,” lead study author Ildiko Lingvay, MD, said. The findings support the use of semaglutide as an alternative to canagliflozin when treatment intensification after metformin is needed, Dr. Lingvay and coauthors concluded in an article published simultaneously in Lancet Diabetes & Endocrinology (2019 Sep 17. doi: 10.1016/S2213-8587[19]30311-0).

Dr. Lingvay of the University of Texas in Dallas observed that both GLP-1 RAs and SGLT2 inhibitors are recommended as second-line treatment after metformin and lifestyle modifications, particularly when there is a need to minimize the risk for hypoglycemia and weight gain, and there is established cardiovascular disease. Despite their wide endorsement, however, there has really been only one other head-to-head trial that evaluated the two drug classes – the PIONEER 2 study, which compared oral semaglutide and the SGLT2 inhibitor empagliflozin (Jardiance). Another trial, DURATION-8, compared the GLP-1 RA exenatide (Byetta) or the SGLT2 inhibitor dapagliflozin (Farxiga) with an exenatide-dapagliflozin combination, but it did not directly compare the two drug classes.

SUSTAIN 8 was a phase 3b, randomized, double-blind, parallel-group, controlled trial that compared once-weekly subcutaneous semaglutide 1.0 mg and daily oral canagliflozin 300 mg as add-on treatments to metformin in 788 individuals with type 2 diabetes. Participants had to have a starting HbA_1c of between 7.0% and 10.0%, to be on a stable dose of metformin, and to have an estimated glomerular filtration rate of 60 mL/min per 1.73 m³ or higher.

Of the 394 patients randomized to semaglutide, 83.3% completed the study treatment and 15.7% discontinued prematurely, most often because of adverse events (9.7%). Of the remaining 394 patients randomized to canagliflozin therapy, 87.1% completed treatment and 12.9% discontinued prematurely, again mostly for adverse events (5.1%).

Overall the rate of any adverse events (76.0% vs. 71.8%) or serious adverse events (4.6% vs. 5.3%) were similar between the semaglutide and canagliflozin groups. As expected, more gastrointestinal side effects were seen in patients treated with semaglutide than in those treated with canagliflozin (46.9% vs. 27.9%), and there were more infections in the canagliflozin group (29.1% vs. 34.5%). Hypoglycemic episodes were “very rare in this population,” Dr. Lingvay reported. Rates of severe or confirmed hypoglycemia were 1.5% and 1.3% for the respective arms.

Other findings of note were improved fasting blood lipids – with greater changes in total serum cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides seen with semaglutide than canagliflozin. Systolic blood pressure dropped in both groups, with a greater change in the canagliflozin than semaglutide group (–5.5 mm Hg vs. –3.5 mm Hg; P = .0452).

In a substudy of SUSTAIN 8 (n = 178), which was reported separately at the meeting, both semaglutide and canagliflozin reduced total fat mass as assessed with whole-body, dual-energy x-ray absorptiometry scanning. The changes in total fat mass from baseline to week 52 were a respective –3.4 kg and –2.6, or 1.4% and 1.2%. Total lean mass changed by a respective –2.3 kg and –1.5 kg (1.2% and 1.1%), and visceral fat mass by –0.2 kg and –0.1 kg (–0.9% and 0.4%). There was no statistical significance between the groups. A post hoc analysis did show, however, that a greater drop in waist circumference might be achieved with semaglutide than with canagliflozin (–4.0 vs. –2.9 cm [–3.9% vs. –2.5%], P = .02).

“Importantly, neither treatment was associated with deleterious body composition changes, such as gains in fat mass or reductions in the total lean mass,” said Rory McCrimmon, MBChB, professor of experimental diabetes and metabolism at the University of Dundee, Scotland, when presenting the substudy findings.

“These findings are consistent with results from other body composition studies with GLP-1 RAs and SGLT2 [inhibitors],”Dr. McCrimmon said, adding that “the positive effects on total fat loss and visceral fat reduction highlight the role of semaglutide and canagliflozin as relevant treatment options for patients with type 2 diabetes.”

Novo Nordisk funded the study. Dr. Lingvay has received consulting fees from Novo Nordisk; research grants from her institution; and grants, personal fees, or both, from other companies not related to the study. Dr. McCrimmon has received personal fees from Novo Nordisk and two other companies.
 

SOURCES: Lingvay I et al. Lancet Diabetes Endocrinol. 2019 Sep 17. doi: 10.1016/S2213-8587(19)30311-0; McCrimmon RJ et al. EASD 2019, Abstract 54.

BARCELONA – The glucagonlike peptide–1 receptor antagonist semaglutide (Ozempic) produced greater reductions in glycated hemoglobin and body weight than the sodium-glucose cotransporter 2 inhibitor canagliflozin (Invokana) in second-line treatment in patients with type 2 diabetes after metformin and lifestyle modifications, researchers reported at the annual meeting of the European Association for the Study of Diabetes.

The year-long SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) 8 trial comparing semaglutide and canagliflozin is one of the few head-to-head comparisons of the glucagonlike peptide–1 receptor antagonist (GLP-1 RA) and sodium-glucose cotransporter 2 (SGLT2) inhibitor classes of drugs.

Findings showed overall changes in HbA_{1c level} from baseline to week 52 of –1.5 percentage points with semaglutide and –1.0 percentage point with canagliflozin, and changes in body weight during the same time of –5.3 kg and –4.2 kg, respectively. The estimated treatment differences were –0.49 percentage points for HbA_1c (P less than .001) and –1.06 kg for body weight (P less than .0029).

A significantly higher percentage of patients receiving semaglutide also achieved HbA_1c targets at 52 weeks, compared with those receiving canagliflozin: 66.1% versus 45.1%, respectively, achieved the American Diabetes Association’s target of less than 7%, and 52.8% versus 23.6% (P less than .0001) reached the lower target of 6.5% or lower, as set by the American Association of Clinical Endocrinologists.

Furthermore, a significantly higher proportion of patients in the semaglutide arm achieved 10% or more weight loss by the end of the study (22.3% vs. 8.9% in the canagliflozin arm; P less than .0001), with a trend for 5% or greater weight loss favoring semaglutide (51.1% vs. 46.6%, P = .21). A post hoc analysis also showed that patients treated with semaglutide could achieve a weight loss of 15% or more (6.8% vs. 0.9% for canagliflozin, P = .0001).

“SUSTAIN 8 provides clinically relevant information regarding the head-to-head comparison of these two very commonly used glucose-lowering classes [of drugs] as second-line therapy in patients with type 2 diabetes,” lead study author Ildiko Lingvay, MD, said. The findings support the use of semaglutide as an alternative to canagliflozin when treatment intensification after metformin is needed, Dr. Lingvay and coauthors concluded in an article published simultaneously in Lancet Diabetes & Endocrinology (2019 Sep 17. doi: 10.1016/S2213-8587[19]30311-0).

Dr. Lingvay of the University of Texas in Dallas observed that both GLP-1 RAs and SGLT2 inhibitors are recommended as second-line treatment after metformin and lifestyle modifications, particularly when there is a need to minimize the risk for hypoglycemia and weight gain, and there is established cardiovascular disease. Despite their wide endorsement, however, there has really been only one other head-to-head trial that evaluated the two drug classes – the PIONEER 2 study, which compared oral semaglutide and the SGLT2 inhibitor empagliflozin (Jardiance). Another trial, DURATION-8, compared the GLP-1 RA exenatide (Byetta) or the SGLT2 inhibitor dapagliflozin (Farxiga) with an exenatide-dapagliflozin combination, but it did not directly compare the two drug classes.

SUSTAIN 8 was a phase 3b, randomized, double-blind, parallel-group, controlled trial that compared once-weekly subcutaneous semaglutide 1.0 mg and daily oral canagliflozin 300 mg as add-on treatments to metformin in 788 individuals with type 2 diabetes. Participants had to have a starting HbA_1c of between 7.0% and 10.0%, to be on a stable dose of metformin, and to have an estimated glomerular filtration rate of 60 mL/min per 1.73 m³ or higher.

Of the 394 patients randomized to semaglutide, 83.3% completed the study treatment and 15.7% discontinued prematurely, most often because of adverse events (9.7%). Of the remaining 394 patients randomized to canagliflozin therapy, 87.1% completed treatment and 12.9% discontinued prematurely, again mostly for adverse events (5.1%).

Overall the rate of any adverse events (76.0% vs. 71.8%) or serious adverse events (4.6% vs. 5.3%) were similar between the semaglutide and canagliflozin groups. As expected, more gastrointestinal side effects were seen in patients treated with semaglutide than in those treated with canagliflozin (46.9% vs. 27.9%), and there were more infections in the canagliflozin group (29.1% vs. 34.5%). Hypoglycemic episodes were “very rare in this population,” Dr. Lingvay reported. Rates of severe or confirmed hypoglycemia were 1.5% and 1.3% for the respective arms.

Other findings of note were improved fasting blood lipids – with greater changes in total serum cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides seen with semaglutide than canagliflozin. Systolic blood pressure dropped in both groups, with a greater change in the canagliflozin than semaglutide group (–5.5 mm Hg vs. –3.5 mm Hg; P = .0452).

In a substudy of SUSTAIN 8 (n = 178), which was reported separately at the meeting, both semaglutide and canagliflozin reduced total fat mass as assessed with whole-body, dual-energy x-ray absorptiometry scanning. The changes in total fat mass from baseline to week 52 were a respective –3.4 kg and –2.6, or 1.4% and 1.2%. Total lean mass changed by a respective –2.3 kg and –1.5 kg (1.2% and 1.1%), and visceral fat mass by –0.2 kg and –0.1 kg (–0.9% and 0.4%). There was no statistical significance between the groups. A post hoc analysis did show, however, that a greater drop in waist circumference might be achieved with semaglutide than with canagliflozin (–4.0 vs. –2.9 cm [–3.9% vs. –2.5%], P = .02).

“Importantly, neither treatment was associated with deleterious body composition changes, such as gains in fat mass or reductions in the total lean mass,” said Rory McCrimmon, MBChB, professor of experimental diabetes and metabolism at the University of Dundee, Scotland, when presenting the substudy findings.

“These findings are consistent with results from other body composition studies with GLP-1 RAs and SGLT2 [inhibitors],”Dr. McCrimmon said, adding that “the positive effects on total fat loss and visceral fat reduction highlight the role of semaglutide and canagliflozin as relevant treatment options for patients with type 2 diabetes.”

Novo Nordisk funded the study. Dr. Lingvay has received consulting fees from Novo Nordisk; research grants from her institution; and grants, personal fees, or both, from other companies not related to the study. Dr. McCrimmon has received personal fees from Novo Nordisk and two other companies.
 

SOURCES: Lingvay I et al. Lancet Diabetes Endocrinol. 2019 Sep 17. doi: 10.1016/S2213-8587(19)30311-0; McCrimmon RJ et al. EASD 2019, Abstract 54.

BARCELONA – The glucagonlike peptide–1 receptor antagonist semaglutide (Ozempic) produced greater reductions in glycated hemoglobin and body weight than the sodium-glucose cotransporter 2 inhibitor canagliflozin (Invokana) in second-line treatment in patients with type 2 diabetes after metformin and lifestyle modifications, researchers reported at the annual meeting of the European Association for the Study of Diabetes.

The year-long SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) 8 trial comparing semaglutide and canagliflozin is one of the few head-to-head comparisons of the glucagonlike peptide–1 receptor antagonist (GLP-1 RA) and sodium-glucose cotransporter 2 (SGLT2) inhibitor classes of drugs.

Findings showed overall changes in HbA_{1c level} from baseline to week 52 of –1.5 percentage points with semaglutide and –1.0 percentage point with canagliflozin, and changes in body weight during the same time of –5.3 kg and –4.2 kg, respectively. The estimated treatment differences were –0.49 percentage points for HbA_1c (P less than .001) and –1.06 kg for body weight (P less than .0029).

A significantly higher percentage of patients receiving semaglutide also achieved HbA_1c targets at 52 weeks, compared with those receiving canagliflozin: 66.1% versus 45.1%, respectively, achieved the American Diabetes Association’s target of less than 7%, and 52.8% versus 23.6% (P less than .0001) reached the lower target of 6.5% or lower, as set by the American Association of Clinical Endocrinologists.

Furthermore, a significantly higher proportion of patients in the semaglutide arm achieved 10% or more weight loss by the end of the study (22.3% vs. 8.9% in the canagliflozin arm; P less than .0001), with a trend for 5% or greater weight loss favoring semaglutide (51.1% vs. 46.6%, P = .21). A post hoc analysis also showed that patients treated with semaglutide could achieve a weight loss of 15% or more (6.8% vs. 0.9% for canagliflozin, P = .0001).

“SUSTAIN 8 provides clinically relevant information regarding the head-to-head comparison of these two very commonly used glucose-lowering classes [of drugs] as second-line therapy in patients with type 2 diabetes,” lead study author Ildiko Lingvay, MD, said. The findings support the use of semaglutide as an alternative to canagliflozin when treatment intensification after metformin is needed, Dr. Lingvay and coauthors concluded in an article published simultaneously in Lancet Diabetes & Endocrinology (2019 Sep 17. doi: 10.1016/S2213-8587[19]30311-0).

Dr. Lingvay of the University of Texas in Dallas observed that both GLP-1 RAs and SGLT2 inhibitors are recommended as second-line treatment after metformin and lifestyle modifications, particularly when there is a need to minimize the risk for hypoglycemia and weight gain, and there is established cardiovascular disease. Despite their wide endorsement, however, there has really been only one other head-to-head trial that evaluated the two drug classes – the PIONEER 2 study, which compared oral semaglutide and the SGLT2 inhibitor empagliflozin (Jardiance). Another trial, DURATION-8, compared the GLP-1 RA exenatide (Byetta) or the SGLT2 inhibitor dapagliflozin (Farxiga) with an exenatide-dapagliflozin combination, but it did not directly compare the two drug classes.

SUSTAIN 8 was a phase 3b, randomized, double-blind, parallel-group, controlled trial that compared once-weekly subcutaneous semaglutide 1.0 mg and daily oral canagliflozin 300 mg as add-on treatments to metformin in 788 individuals with type 2 diabetes. Participants had to have a starting HbA_1c of between 7.0% and 10.0%, to be on a stable dose of metformin, and to have an estimated glomerular filtration rate of 60 mL/min per 1.73 m³ or higher.

Of the 394 patients randomized to semaglutide, 83.3% completed the study treatment and 15.7% discontinued prematurely, most often because of adverse events (9.7%). Of the remaining 394 patients randomized to canagliflozin therapy, 87.1% completed treatment and 12.9% discontinued prematurely, again mostly for adverse events (5.1%).

Overall the rate of any adverse events (76.0% vs. 71.8%) or serious adverse events (4.6% vs. 5.3%) were similar between the semaglutide and canagliflozin groups. As expected, more gastrointestinal side effects were seen in patients treated with semaglutide than in those treated with canagliflozin (46.9% vs. 27.9%), and there were more infections in the canagliflozin group (29.1% vs. 34.5%). Hypoglycemic episodes were “very rare in this population,” Dr. Lingvay reported. Rates of severe or confirmed hypoglycemia were 1.5% and 1.3% for the respective arms.

Other findings of note were improved fasting blood lipids – with greater changes in total serum cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides seen with semaglutide than canagliflozin. Systolic blood pressure dropped in both groups, with a greater change in the canagliflozin than semaglutide group (–5.5 mm Hg vs. –3.5 mm Hg; P = .0452).

In a substudy of SUSTAIN 8 (n = 178), which was reported separately at the meeting, both semaglutide and canagliflozin reduced total fat mass as assessed with whole-body, dual-energy x-ray absorptiometry scanning. The changes in total fat mass from baseline to week 52 were a respective –3.4 kg and –2.6, or 1.4% and 1.2%. Total lean mass changed by a respective –2.3 kg and –1.5 kg (1.2% and 1.1%), and visceral fat mass by –0.2 kg and –0.1 kg (–0.9% and 0.4%). There was no statistical significance between the groups. A post hoc analysis did show, however, that a greater drop in waist circumference might be achieved with semaglutide than with canagliflozin (–4.0 vs. –2.9 cm [–3.9% vs. –2.5%], P = .02).

“Importantly, neither treatment was associated with deleterious body composition changes, such as gains in fat mass or reductions in the total lean mass,” said Rory McCrimmon, MBChB, professor of experimental diabetes and metabolism at the University of Dundee, Scotland, when presenting the substudy findings.

“These findings are consistent with results from other body composition studies with GLP-1 RAs and SGLT2 [inhibitors],”Dr. McCrimmon said, adding that “the positive effects on total fat loss and visceral fat reduction highlight the role of semaglutide and canagliflozin as relevant treatment options for patients with type 2 diabetes.”

Novo Nordisk funded the study. Dr. Lingvay has received consulting fees from Novo Nordisk; research grants from her institution; and grants, personal fees, or both, from other companies not related to the study. Dr. McCrimmon has received personal fees from Novo Nordisk and two other companies.
 

SOURCES: Lingvay I et al. Lancet Diabetes Endocrinol. 2019 Sep 17. doi: 10.1016/S2213-8587(19)30311-0; McCrimmon RJ et al. EASD 2019, Abstract 54.

BARCELONA – Upfront use of a dual combination of vildagliptin (Galvus) and metformin was associated with better and more durable glycemic control than metformin alone in patients with newly diagnosed type 2 diabetes, according to findings reported at the annual meeting of the European Association for the Study of Diabetes.

Fewer patients treated with the combination than with metformin monotherapy experienced “treatment failure” (43.6% vs. 62.1%, respectively) during the initial study period. The time-to-treatment failure, which was defined as an hemoglobin A_1c of at least 7% (53 mmol/L) or higher on two occasions 3 months apart, was estimated to be beyond the study’s duration, at 61·9 months, for the combination and a median of 36.1 months in the monotherapy group.

Moreover, there was a significant (P less than .0001) 49% reduction in the relative risk for the time-to-initial-treatment failure in the early combination treatment group, compared with the monotherapy group, during the 5-year study period. The time-to-second-treatment failure was also longer in patients who received initial combination therapy (hazard ratio, 0.74; P less than .0001).

These results of the VERIFY (Vildagliptin Efficacy in Combination With Metformin for Early Treatment of Type 2 Diabetes) study, which were published simultaneously in the Lancet, provide the first real evidence to support the use of combination therapy rather than the current standard of metformin alone in the initial treatment of type 2 diabetes.

VERIFY was a phase 4, randomized, parallel-group study designed to compare the durability of glycemic control achieved with a combination of vildagliptin plus metformin or metformin alone in treatment-naive patients with type 2 diabetes.

At a press briefing, three members of the VERITY steering committee explained the rationale, design, results, and implications of the study.

EASD president David R. Matthews, DPhil, FRCP, who is emeritus professor at the Oxford Centre for Diabetes, Endocrinology and Metabolism at the University of Oxford (England), observed that the study aimed to answer three important questions: Do patients with type 2 diabetes benefit from having combination treatment from the start of their pharmacologic management, and if so, is this more beneficial than a step-up approach, and ultimately, “does it really matter?”

Sara Freeman/MDedge News

A typical cohort of patients was included, said Michael Stumvoll, MD, of the University Hospital Leipzig (Germany). Patients had to be aged between 18 and 70 years, have a body mass index of 22-40 kg/m², and an hemoglobin A_1c level of 6.5%-7.5%. This “rather narrow range” was decided “on purpose to really fulfill the idea of having newly diagnosed [type 2 diabetes]”, Dr. Stumvoll noted. In addition, patients had to have adequate renal function, have been diagnosed with type 2 diabetes in the past 2 years, and be drug naive or have received no more than 4 weeks of metformin.

In all, 2,001 patients from 254 centers in 34 countries were included, with 998 randomized to initial treatment with vildagliptin and metformin and 1,003 to receive metformin alone after an initial run-in phase during which the dose of metformin was up-titrated from 500 to 1,500 mg/day. The study ran for 5 years, with treatment intensified if there was a loss of glycemic control at the discretion of the study investigators – first vildagliptin was added to patients taking metformin monotherapy, then insulin, if needed.

There were no safety concerns: A similar percentage of patients in the early combination and initial monotherapy arms experienced an adverse event (83.5% vs. 83.2%, respectively), a serious adverse event (16.6% vs. 18.3%), a drug-related adverse event (15.9% vs. 14.3%), a severe adverse event (10.5% vs. 10.6%), and adverse events leading to discontinuation of treatment (4.1% vs. 5.3%) or death (13 vs. 9 patients). There was no difference in the change in body weight, and rates of hypoglycemia were 1.3% and 0.9%, respectively.

Adjudication and an independent data-monitoring committee were set up after cardiovascular events occurred in a few patients, although this was not a cardiovascular outcomes trials, Dr. Matthews stressed. There were fewer absolute cumulative adjudicated events in the early combination arm, compared with the initial monotherapy arm (30 vs. 44, respectively), and the time to the first adjudicated macrovascular event favored early combination over initial monotherapy (2.4% vs. 3.3%; HR, 0.71).

“There is a big caveat here,” said Dr. Matthews, “these are very small numbers and wide confidence intervals and the P value is .194.” Although “it is not a significant finding, and it was never intended to be a significant finding,” it gives “an indication that we absolutely should be looking at this.”

Sara Freeman/MDedge News

Stefano Del Prato, MD, of the University of Pisa (Italy), noted that “there has been a lot of discussion around initial combination therapy for type 2 diabetes,” and although there was a realization that multiple treatment might be necessary, there was no evidence for that. The results of the VERIFY trial, however, now provide some of the proof that this approach may be of benefit. Patients “benefit twice as much” with the combination therapy as they do with the monotherapy, Dr. Del Prato said. “There are twice as many patients retained under control with an early combination, compared with the monotherapy.” That means no longer “running after the patient losing control” he said, but “being proactive” and with a very low risk of hypoglycemia. The clinical implication is that there is now evidence for combination therapy as an initial approach for managing type 2 diabetes.

Novartis funded the study. Dr. Matthews has served on advisory boards or as a consultant for, and has given lectures for, Novartis and numerous other companies not related to the study. He is currently the president of the European Association for the Study of Diabetes. Dr. Stumvoll has received speaker's honoraria and consulting fees from Novartis and other companies. Dr. Del Prato serves or has served on advisory boards and speakers bureaus for, and received research support from, Novartis and numerous other companies.

SOURCE: Matthews DR et al. Lancet. 2019 Sept 18. doi: 10.1016/ S0140-6736(19)32131-2.

This article was updated on 9/19/2019.

BARCELONA – Upfront use of a dual combination of vildagliptin (Galvus) and metformin was associated with better and more durable glycemic control than metformin alone in patients with newly diagnosed type 2 diabetes, according to findings reported at the annual meeting of the European Association for the Study of Diabetes.

Fewer patients treated with the combination than with metformin monotherapy experienced “treatment failure” (43.6% vs. 62.1%, respectively) during the initial study period. The time-to-treatment failure, which was defined as an hemoglobin A_1c of at least 7% (53 mmol/L) or higher on two occasions 3 months apart, was estimated to be beyond the study’s duration, at 61·9 months, for the combination and a median of 36.1 months in the monotherapy group.

Moreover, there was a significant (P less than .0001) 49% reduction in the relative risk for the time-to-initial-treatment failure in the early combination treatment group, compared with the monotherapy group, during the 5-year study period. The time-to-second-treatment failure was also longer in patients who received initial combination therapy (hazard ratio, 0.74; P less than .0001).

These results of the VERIFY (Vildagliptin Efficacy in Combination With Metformin for Early Treatment of Type 2 Diabetes) study, which were published simultaneously in the Lancet, provide the first real evidence to support the use of combination therapy rather than the current standard of metformin alone in the initial treatment of type 2 diabetes.

VERIFY was a phase 4, randomized, parallel-group study designed to compare the durability of glycemic control achieved with a combination of vildagliptin plus metformin or metformin alone in treatment-naive patients with type 2 diabetes.

At a press briefing, three members of the VERITY steering committee explained the rationale, design, results, and implications of the study.

EASD president David R. Matthews, DPhil, FRCP, who is emeritus professor at the Oxford Centre for Diabetes, Endocrinology and Metabolism at the University of Oxford (England), observed that the study aimed to answer three important questions: Do patients with type 2 diabetes benefit from having combination treatment from the start of their pharmacologic management, and if so, is this more beneficial than a step-up approach, and ultimately, “does it really matter?”

Sara Freeman/MDedge News

A typical cohort of patients was included, said Michael Stumvoll, MD, of the University Hospital Leipzig (Germany). Patients had to be aged between 18 and 70 years, have a body mass index of 22-40 kg/m², and an hemoglobin A_1c level of 6.5%-7.5%. This “rather narrow range” was decided “on purpose to really fulfill the idea of having newly diagnosed [type 2 diabetes]”, Dr. Stumvoll noted. In addition, patients had to have adequate renal function, have been diagnosed with type 2 diabetes in the past 2 years, and be drug naive or have received no more than 4 weeks of metformin.

In all, 2,001 patients from 254 centers in 34 countries were included, with 998 randomized to initial treatment with vildagliptin and metformin and 1,003 to receive metformin alone after an initial run-in phase during which the dose of metformin was up-titrated from 500 to 1,500 mg/day. The study ran for 5 years, with treatment intensified if there was a loss of glycemic control at the discretion of the study investigators – first vildagliptin was added to patients taking metformin monotherapy, then insulin, if needed.

There were no safety concerns: A similar percentage of patients in the early combination and initial monotherapy arms experienced an adverse event (83.5% vs. 83.2%, respectively), a serious adverse event (16.6% vs. 18.3%), a drug-related adverse event (15.9% vs. 14.3%), a severe adverse event (10.5% vs. 10.6%), and adverse events leading to discontinuation of treatment (4.1% vs. 5.3%) or death (13 vs. 9 patients). There was no difference in the change in body weight, and rates of hypoglycemia were 1.3% and 0.9%, respectively.

Adjudication and an independent data-monitoring committee were set up after cardiovascular events occurred in a few patients, although this was not a cardiovascular outcomes trials, Dr. Matthews stressed. There were fewer absolute cumulative adjudicated events in the early combination arm, compared with the initial monotherapy arm (30 vs. 44, respectively), and the time to the first adjudicated macrovascular event favored early combination over initial monotherapy (2.4% vs. 3.3%; HR, 0.71).

“There is a big caveat here,” said Dr. Matthews, “these are very small numbers and wide confidence intervals and the P value is .194.” Although “it is not a significant finding, and it was never intended to be a significant finding,” it gives “an indication that we absolutely should be looking at this.”

Sara Freeman/MDedge News

Stefano Del Prato, MD, of the University of Pisa (Italy), noted that “there has been a lot of discussion around initial combination therapy for type 2 diabetes,” and although there was a realization that multiple treatment might be necessary, there was no evidence for that. The results of the VERIFY trial, however, now provide some of the proof that this approach may be of benefit. Patients “benefit twice as much” with the combination therapy as they do with the monotherapy, Dr. Del Prato said. “There are twice as many patients retained under control with an early combination, compared with the monotherapy.” That means no longer “running after the patient losing control” he said, but “being proactive” and with a very low risk of hypoglycemia. The clinical implication is that there is now evidence for combination therapy as an initial approach for managing type 2 diabetes.

Novartis funded the study. Dr. Matthews has served on advisory boards or as a consultant for, and has given lectures for, Novartis and numerous other companies not related to the study. He is currently the president of the European Association for the Study of Diabetes. Dr. Stumvoll has received speaker's honoraria and consulting fees from Novartis and other companies. Dr. Del Prato serves or has served on advisory boards and speakers bureaus for, and received research support from, Novartis and numerous other companies.

SOURCE: Matthews DR et al. Lancet. 2019 Sept 18. doi: 10.1016/ S0140-6736(19)32131-2.

This article was updated on 9/19/2019.

BARCELONA – Upfront use of a dual combination of vildagliptin (Galvus) and metformin was associated with better and more durable glycemic control than metformin alone in patients with newly diagnosed type 2 diabetes, according to findings reported at the annual meeting of the European Association for the Study of Diabetes.

Fewer patients treated with the combination than with metformin monotherapy experienced “treatment failure” (43.6% vs. 62.1%, respectively) during the initial study period. The time-to-treatment failure, which was defined as an hemoglobin A_1c of at least 7% (53 mmol/L) or higher on two occasions 3 months apart, was estimated to be beyond the study’s duration, at 61·9 months, for the combination and a median of 36.1 months in the monotherapy group.

Moreover, there was a significant (P less than .0001) 49% reduction in the relative risk for the time-to-initial-treatment failure in the early combination treatment group, compared with the monotherapy group, during the 5-year study period. The time-to-second-treatment failure was also longer in patients who received initial combination therapy (hazard ratio, 0.74; P less than .0001).

These results of the VERIFY (Vildagliptin Efficacy in Combination With Metformin for Early Treatment of Type 2 Diabetes) study, which were published simultaneously in the Lancet, provide the first real evidence to support the use of combination therapy rather than the current standard of metformin alone in the initial treatment of type 2 diabetes.

VERIFY was a phase 4, randomized, parallel-group study designed to compare the durability of glycemic control achieved with a combination of vildagliptin plus metformin or metformin alone in treatment-naive patients with type 2 diabetes.

At a press briefing, three members of the VERITY steering committee explained the rationale, design, results, and implications of the study.

EASD president David R. Matthews, DPhil, FRCP, who is emeritus professor at the Oxford Centre for Diabetes, Endocrinology and Metabolism at the University of Oxford (England), observed that the study aimed to answer three important questions: Do patients with type 2 diabetes benefit from having combination treatment from the start of their pharmacologic management, and if so, is this more beneficial than a step-up approach, and ultimately, “does it really matter?”

Sara Freeman/MDedge News

A typical cohort of patients was included, said Michael Stumvoll, MD, of the University Hospital Leipzig (Germany). Patients had to be aged between 18 and 70 years, have a body mass index of 22-40 kg/m², and an hemoglobin A_1c level of 6.5%-7.5%. This “rather narrow range” was decided “on purpose to really fulfill the idea of having newly diagnosed [type 2 diabetes]”, Dr. Stumvoll noted. In addition, patients had to have adequate renal function, have been diagnosed with type 2 diabetes in the past 2 years, and be drug naive or have received no more than 4 weeks of metformin.

In all, 2,001 patients from 254 centers in 34 countries were included, with 998 randomized to initial treatment with vildagliptin and metformin and 1,003 to receive metformin alone after an initial run-in phase during which the dose of metformin was up-titrated from 500 to 1,500 mg/day. The study ran for 5 years, with treatment intensified if there was a loss of glycemic control at the discretion of the study investigators – first vildagliptin was added to patients taking metformin monotherapy, then insulin, if needed.

There were no safety concerns: A similar percentage of patients in the early combination and initial monotherapy arms experienced an adverse event (83.5% vs. 83.2%, respectively), a serious adverse event (16.6% vs. 18.3%), a drug-related adverse event (15.9% vs. 14.3%), a severe adverse event (10.5% vs. 10.6%), and adverse events leading to discontinuation of treatment (4.1% vs. 5.3%) or death (13 vs. 9 patients). There was no difference in the change in body weight, and rates of hypoglycemia were 1.3% and 0.9%, respectively.

Adjudication and an independent data-monitoring committee were set up after cardiovascular events occurred in a few patients, although this was not a cardiovascular outcomes trials, Dr. Matthews stressed. There were fewer absolute cumulative adjudicated events in the early combination arm, compared with the initial monotherapy arm (30 vs. 44, respectively), and the time to the first adjudicated macrovascular event favored early combination over initial monotherapy (2.4% vs. 3.3%; HR, 0.71).

“There is a big caveat here,” said Dr. Matthews, “these are very small numbers and wide confidence intervals and the P value is .194.” Although “it is not a significant finding, and it was never intended to be a significant finding,” it gives “an indication that we absolutely should be looking at this.”

Sara Freeman/MDedge News

Stefano Del Prato, MD, of the University of Pisa (Italy), noted that “there has been a lot of discussion around initial combination therapy for type 2 diabetes,” and although there was a realization that multiple treatment might be necessary, there was no evidence for that. The results of the VERIFY trial, however, now provide some of the proof that this approach may be of benefit. Patients “benefit twice as much” with the combination therapy as they do with the monotherapy, Dr. Del Prato said. “There are twice as many patients retained under control with an early combination, compared with the monotherapy.” That means no longer “running after the patient losing control” he said, but “being proactive” and with a very low risk of hypoglycemia. The clinical implication is that there is now evidence for combination therapy as an initial approach for managing type 2 diabetes.

Novartis funded the study. Dr. Matthews has served on advisory boards or as a consultant for, and has given lectures for, Novartis and numerous other companies not related to the study. He is currently the president of the European Association for the Study of Diabetes. Dr. Stumvoll has received speaker's honoraria and consulting fees from Novartis and other companies. Dr. Del Prato serves or has served on advisory boards and speakers bureaus for, and received research support from, Novartis and numerous other companies.

SOURCE: Matthews DR et al. Lancet. 2019 Sept 18. doi: 10.1016/ S0140-6736(19)32131-2.

This article was updated on 9/19/2019.