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CV outcomes better with SGLT2 inhibitor than DPP4 inhibitor in T2DM study
LISBON – The sodium-glucose co-transporter 2 (SGLT-2) inhibitor dapagliflozin (Farxiga) posed a lower risk of cardiovascular events and all-cause mortality in patients with type 2 diabetes mellitus (T2DM) compared with dipeptidyl peptidase-4 inhibitors in a large real-world, observational study.
In CVD-REAL NORDIC, treatment with the SGLT-2 inhibitor reduced the incidence of major cardiovascular adverse events by 21% as compared to DDP-4 inhibitors (hazard ratio, 0.79; 95% confidence interval, 0.67-0.94; P = .006).
Anna Norhammar, MD, PhD, of the Institute of Medicine, Cardiology Unit, at Karolinska Institutet in Stockholm, presented the findings at the annual meeting of the European Association for the Study of Diabetes.
She said: “These results are in line with previous clinical trials and meta-analyses, but extend the results to a broader CV risk population and with a commonly used comparator.”
Indeed, the findings build on those from the widely reported EMPA-REG Outcome (New Engl J Med. 2015;373;2117-8) and CANVAS (New Engl J Med. 2017;377:644-7) randomized controlled trials. These trials respectively showed empagliflozin and canagliflozin significantly reduced the risk for MACE and heart failure in patients with T2DM versus placebo. As the majority of patients in these trials had established CV disease, this suggested a class effect for SGLT2 inhibitors, Dr. Norhammar explained.
CVD-REAL NORDIC is part of a larger, multinational, observational, comparative effectiveness study looking at the real-world effect of SGLT2 inhibitors versus other glucose-lowering drugs on CV outcomes in patients with T2DM. Altogether around 90,000 patients have been recruited in Sweden, Norway, and Denmark.
Previously, Dr. Norhammar and co-investigators have reported that SGLT2 inhibitors lowered MACE (HR, 0.78; 95% CI 0.69–0.87, P less than .0001) and heart failure hospitalization (HR, 0.70; 95% CI 0.61–0.81, P less than .0001) relative to all glucose-lowering drugs (Lancet Diabetes Endocrinol. 2017;709–17).
“However, the comparator group used in that study, other [glucose-lowering drugs], consisted of almost 50% patients with T2DM treated with insulin or sul[f]onylureas,” they wrote in Diabetes, Obesity and Metabolism (8 Sep., doi: 10.1111/dom.13077). Insulin or sulfonylureas, they add, “have been shown to have increased associated CV risks” compared with DPP4 inhibitors and it is “not fully clear to what extent this could have influenced risk estimates.”
Furthermore, the CVD-NORDIC investigators note that the comparator group reflected real-world practice and it is important to look at treatment strategies more specifically, hence why they decided to do an analysis comparing SGLT2 and DPP4 inhibitors.
The study population for the current analysis consisted of 40,909 patients with T2DM who were newly initiated on either dapagliflozin (n=10,227) or a DPP4 inhibitor (n=30,682) between 2012 and 2015. The mean age was 61 years, and around 23% had prior CV disease and 5% had previous heart failure.
After a mean follow-up of 11.3 months, 177 MACE events had occurred among the 10,227 dapagliflozin-treated patients and 695 among the 30,681 DPP4 inhibitor-treated patients, giving respective event rates of 1.86 and 2.34 per 100 patient years. MACE was defined as a composite of nonfatal myocardial infarction, nonfatal stroke, and CV mortality.
“Dapagliflozin is the most commonly used SGLT2 inhibitor in the Nordic countries,” Dr. Norhammar said, explaining why this particular SGLT2 inhibitor was used in the analysis.
While there was a clear benefit of using dapagliflozin over DPP4 inhibitors in terms of MACE, heart failure hospitalization, and all-cause mortality, there was a “neutral” effect on atrial fibrillation and severe hypoglycaemia, with respective HRs of 0.92 (95% CI 0.76–1.12; P = .41) and 0.94 (95% CI 0.74–1.19; P = .62).
Dr. Norhammar said these “neutral results for atrial fibrillation and severe hypoglycaemia,” were “in line with expectations, and suggest a low likelihood of confounding.”
As this was an observational study, one of the limitations is that could be confounding factors that could not be adequately matched in the analysis. The events were not adjudicated and the study didn’t look at safety.
Dr. Norhammar noted that the results of the DECLARE-TIMI 58 trials were now needed to see if the potential CV benefits of using an SGLT2 inhibitor over other gluc0se-lowering medications might extend into patients at lower CV risk.
AstraZeneca supported the study.
Dr. Norhammar disclosed acting as a consultant to and receiving honoraria from AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Novo Nordisk, and MSD Sweden.
LISBON – The sodium-glucose co-transporter 2 (SGLT-2) inhibitor dapagliflozin (Farxiga) posed a lower risk of cardiovascular events and all-cause mortality in patients with type 2 diabetes mellitus (T2DM) compared with dipeptidyl peptidase-4 inhibitors in a large real-world, observational study.
In CVD-REAL NORDIC, treatment with the SGLT-2 inhibitor reduced the incidence of major cardiovascular adverse events by 21% as compared to DDP-4 inhibitors (hazard ratio, 0.79; 95% confidence interval, 0.67-0.94; P = .006).
Anna Norhammar, MD, PhD, of the Institute of Medicine, Cardiology Unit, at Karolinska Institutet in Stockholm, presented the findings at the annual meeting of the European Association for the Study of Diabetes.
She said: “These results are in line with previous clinical trials and meta-analyses, but extend the results to a broader CV risk population and with a commonly used comparator.”
Indeed, the findings build on those from the widely reported EMPA-REG Outcome (New Engl J Med. 2015;373;2117-8) and CANVAS (New Engl J Med. 2017;377:644-7) randomized controlled trials. These trials respectively showed empagliflozin and canagliflozin significantly reduced the risk for MACE and heart failure in patients with T2DM versus placebo. As the majority of patients in these trials had established CV disease, this suggested a class effect for SGLT2 inhibitors, Dr. Norhammar explained.
CVD-REAL NORDIC is part of a larger, multinational, observational, comparative effectiveness study looking at the real-world effect of SGLT2 inhibitors versus other glucose-lowering drugs on CV outcomes in patients with T2DM. Altogether around 90,000 patients have been recruited in Sweden, Norway, and Denmark.
Previously, Dr. Norhammar and co-investigators have reported that SGLT2 inhibitors lowered MACE (HR, 0.78; 95% CI 0.69–0.87, P less than .0001) and heart failure hospitalization (HR, 0.70; 95% CI 0.61–0.81, P less than .0001) relative to all glucose-lowering drugs (Lancet Diabetes Endocrinol. 2017;709–17).
“However, the comparator group used in that study, other [glucose-lowering drugs], consisted of almost 50% patients with T2DM treated with insulin or sul[f]onylureas,” they wrote in Diabetes, Obesity and Metabolism (8 Sep., doi: 10.1111/dom.13077). Insulin or sulfonylureas, they add, “have been shown to have increased associated CV risks” compared with DPP4 inhibitors and it is “not fully clear to what extent this could have influenced risk estimates.”
Furthermore, the CVD-NORDIC investigators note that the comparator group reflected real-world practice and it is important to look at treatment strategies more specifically, hence why they decided to do an analysis comparing SGLT2 and DPP4 inhibitors.
The study population for the current analysis consisted of 40,909 patients with T2DM who were newly initiated on either dapagliflozin (n=10,227) or a DPP4 inhibitor (n=30,682) between 2012 and 2015. The mean age was 61 years, and around 23% had prior CV disease and 5% had previous heart failure.
After a mean follow-up of 11.3 months, 177 MACE events had occurred among the 10,227 dapagliflozin-treated patients and 695 among the 30,681 DPP4 inhibitor-treated patients, giving respective event rates of 1.86 and 2.34 per 100 patient years. MACE was defined as a composite of nonfatal myocardial infarction, nonfatal stroke, and CV mortality.
“Dapagliflozin is the most commonly used SGLT2 inhibitor in the Nordic countries,” Dr. Norhammar said, explaining why this particular SGLT2 inhibitor was used in the analysis.
While there was a clear benefit of using dapagliflozin over DPP4 inhibitors in terms of MACE, heart failure hospitalization, and all-cause mortality, there was a “neutral” effect on atrial fibrillation and severe hypoglycaemia, with respective HRs of 0.92 (95% CI 0.76–1.12; P = .41) and 0.94 (95% CI 0.74–1.19; P = .62).
Dr. Norhammar said these “neutral results for atrial fibrillation and severe hypoglycaemia,” were “in line with expectations, and suggest a low likelihood of confounding.”
As this was an observational study, one of the limitations is that could be confounding factors that could not be adequately matched in the analysis. The events were not adjudicated and the study didn’t look at safety.
Dr. Norhammar noted that the results of the DECLARE-TIMI 58 trials were now needed to see if the potential CV benefits of using an SGLT2 inhibitor over other gluc0se-lowering medications might extend into patients at lower CV risk.
AstraZeneca supported the study.
Dr. Norhammar disclosed acting as a consultant to and receiving honoraria from AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Novo Nordisk, and MSD Sweden.
LISBON – The sodium-glucose co-transporter 2 (SGLT-2) inhibitor dapagliflozin (Farxiga) posed a lower risk of cardiovascular events and all-cause mortality in patients with type 2 diabetes mellitus (T2DM) compared with dipeptidyl peptidase-4 inhibitors in a large real-world, observational study.
In CVD-REAL NORDIC, treatment with the SGLT-2 inhibitor reduced the incidence of major cardiovascular adverse events by 21% as compared to DDP-4 inhibitors (hazard ratio, 0.79; 95% confidence interval, 0.67-0.94; P = .006).
Anna Norhammar, MD, PhD, of the Institute of Medicine, Cardiology Unit, at Karolinska Institutet in Stockholm, presented the findings at the annual meeting of the European Association for the Study of Diabetes.
She said: “These results are in line with previous clinical trials and meta-analyses, but extend the results to a broader CV risk population and with a commonly used comparator.”
Indeed, the findings build on those from the widely reported EMPA-REG Outcome (New Engl J Med. 2015;373;2117-8) and CANVAS (New Engl J Med. 2017;377:644-7) randomized controlled trials. These trials respectively showed empagliflozin and canagliflozin significantly reduced the risk for MACE and heart failure in patients with T2DM versus placebo. As the majority of patients in these trials had established CV disease, this suggested a class effect for SGLT2 inhibitors, Dr. Norhammar explained.
CVD-REAL NORDIC is part of a larger, multinational, observational, comparative effectiveness study looking at the real-world effect of SGLT2 inhibitors versus other glucose-lowering drugs on CV outcomes in patients with T2DM. Altogether around 90,000 patients have been recruited in Sweden, Norway, and Denmark.
Previously, Dr. Norhammar and co-investigators have reported that SGLT2 inhibitors lowered MACE (HR, 0.78; 95% CI 0.69–0.87, P less than .0001) and heart failure hospitalization (HR, 0.70; 95% CI 0.61–0.81, P less than .0001) relative to all glucose-lowering drugs (Lancet Diabetes Endocrinol. 2017;709–17).
“However, the comparator group used in that study, other [glucose-lowering drugs], consisted of almost 50% patients with T2DM treated with insulin or sul[f]onylureas,” they wrote in Diabetes, Obesity and Metabolism (8 Sep., doi: 10.1111/dom.13077). Insulin or sulfonylureas, they add, “have been shown to have increased associated CV risks” compared with DPP4 inhibitors and it is “not fully clear to what extent this could have influenced risk estimates.”
Furthermore, the CVD-NORDIC investigators note that the comparator group reflected real-world practice and it is important to look at treatment strategies more specifically, hence why they decided to do an analysis comparing SGLT2 and DPP4 inhibitors.
The study population for the current analysis consisted of 40,909 patients with T2DM who were newly initiated on either dapagliflozin (n=10,227) or a DPP4 inhibitor (n=30,682) between 2012 and 2015. The mean age was 61 years, and around 23% had prior CV disease and 5% had previous heart failure.
After a mean follow-up of 11.3 months, 177 MACE events had occurred among the 10,227 dapagliflozin-treated patients and 695 among the 30,681 DPP4 inhibitor-treated patients, giving respective event rates of 1.86 and 2.34 per 100 patient years. MACE was defined as a composite of nonfatal myocardial infarction, nonfatal stroke, and CV mortality.
“Dapagliflozin is the most commonly used SGLT2 inhibitor in the Nordic countries,” Dr. Norhammar said, explaining why this particular SGLT2 inhibitor was used in the analysis.
While there was a clear benefit of using dapagliflozin over DPP4 inhibitors in terms of MACE, heart failure hospitalization, and all-cause mortality, there was a “neutral” effect on atrial fibrillation and severe hypoglycaemia, with respective HRs of 0.92 (95% CI 0.76–1.12; P = .41) and 0.94 (95% CI 0.74–1.19; P = .62).
Dr. Norhammar said these “neutral results for atrial fibrillation and severe hypoglycaemia,” were “in line with expectations, and suggest a low likelihood of confounding.”
As this was an observational study, one of the limitations is that could be confounding factors that could not be adequately matched in the analysis. The events were not adjudicated and the study didn’t look at safety.
Dr. Norhammar noted that the results of the DECLARE-TIMI 58 trials were now needed to see if the potential CV benefits of using an SGLT2 inhibitor over other gluc0se-lowering medications might extend into patients at lower CV risk.
AstraZeneca supported the study.
Dr. Norhammar disclosed acting as a consultant to and receiving honoraria from AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Novo Nordisk, and MSD Sweden.
AT EASD 2017
Key clinical point:
Major finding: Hazard ratios for MACE, heart failure hospitalization, and all-cause mortality were a respective 0.79, 0.62, and 0.59, comparing SGLT2 with DPP4 inhibitors.
Data source: CVD-NORDIC, part of a multinational, observational study comparing the real-world effect of SGLT2 inhibitors versus other glucose-lowering drugs on CV outcomes in patients with T2DM.
Disclosures: AstraZeneca supported the study. The presenting author disclosed acting as a consultant to and receiving honoraria from AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Novo Nordisk, and MSD Sweden.
Care needed using sotagliflozin as add-on to insulin in T1DM
LISBON – Further phase 3 trial data show that the investigational dual sodium-glucose cotransporter 1 and 2 (SGLT1/2) inhibitor according to results reported at the annual meeting of the European Association for the Study of Diabetes.
In the inTandem3 trial, 28.6% of 699 people with T1DM treated with sotagliflozin on top of their usual insulin therapy achieved the primary composite endpoint, which was a glycated hemoglobin (HbA1c) level of 7% or lower at Week 24, with no episodes of severe hypoglycemia or diabetic ketoacidosis (DKA). In comparison, 15.2% of the 703 individuals who received a placebo in addition to their insulin therapy achieved this endpoint (P less than .001), according to Melanie J. Davies, MD, who presented the inTandem3 study results during a symposium on the sotagliflozin clinical program. The results were published online in the New England Journal of Medicine (2017 Sep 15. doi: 10.1056/NEJMoa1708337) to coincide with their presentation at the meeting.
However, the overall rate of DKA was higher in the patients treated with sotagliflozin than in those on placebo, at 3% versus 0.6%, respectively. DKA events most often occurred in persons using insulin pumps (4.4% vs. 9.7%) than in those taking insulin via multiple daily injections (2.1% vs 0.5%). Furthermore, in a post-hoc analysis, it was found that the rate of at least one episode of DKA was significantly higher in sotagliflozin- than placebo-treated patients who failed to reach the HbA1c target of below 7% (P less than .003), reported Dr. Davies.
The study findings “build on data seen inTandem 1 and inTandem 2 but in a more pragmatic design,” said study investigator Melanie Davies, MD, professor of diabetes medicine at the University of Leicester (England).
The inTandem studies
Dr. Davies observed that the sotagliflozin clinical trials program in persons with T1DM involved three phase 2 and three phase 3 studies. The latter, inTandem1, inTandem2, and inTandem3, were all 24-week trials, but there were some differences in the design.
inTandem1 and inTandem2 were the pivotal studies, one conducted in 793 patients in North America and the other in 782 patients in Europe and Israel. After a 2-week screening period, participants underwent a 6-week insulin optimization program before they were randomized to one of two doses of sotagliflozin (200 mg or 400 mg) or placebo for 24 weeks, with follow-up out to 52 weeks. The primary endpoint of these studies was the reduction in HbA1c versus placebo at 24 weeks.
By comparison, inTandem3 was a global study involving 1,405 individuals with T1DM who did not undergo the 6-week insulin optimization period. Instead there was a 2-week run-in period after the initial screening, and the study ran for only 24 weeks. Only one dose (400 mg) of sotagliflozin was used and the primary endpoint was a composite to try to see what the net clinical benefit would be, Dr. Davies explained.
The results of inTandem1 and inTandem2 were reported earlier this year at the American Diabetes Association Scientific Sessions, Dr. Davies noted, and sotagliflozin had “a good efficacy and safety profile as an adjunct to insulin in type 1 diabetes.”
The quest for adjunctive treatment
“For years we’ve been looking for adjunctive therapy for people with type 1 diabetes,” said Julio Rosenstock, MD, at the EASD meeting. Dr. Rosenstock, who is the director of the Dallas Diabetes Research Center at Medical City and involved in the sotagliflozin clinical trials program, noted that the quest for an adjunctive treatment was because “glucose control in type 1 diabetes remains tough and costly, despite multiple advances in insulin therapy, delivery systems, and monitoring methods over the years.”
Several approaches to adjunctive treatment had been proposed, but so far all with limited value, Dr. Rosenstock maintained. Despite no evidence for a benefit of adding metformin, for example, registry data suggest that up to 5% of people with T1DM are using it.
The recent findings of the REMOVAL trial showed metformin did not help change the HbA1c over time and there was no change in the primary outcome, he observed but a small improvement in a tertiary endpoint. “I can’t think of a more negative cardiovascular outcomes trial,” Dr. Rosenstock asserted. “There is not enough justification to use metformin in type 1 diabetes.”
By contrast there is a strong rationale for using SGLT inhibition, partly as the glucose-lowering effects are independent of insulin’s activity. Through inhibition of SGLT1, sotagliflozin reduces glucose absorption in the proximal intestine, thus blunting or delaying rising postprandial glucose levels. By also targeting SGLT2, sotagliflozin can reduce glucose resorption by the kidneys.
Risks and clinical implications
In an editorial accompanying the published findings, David Nathan, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, is not convinced that using adjunctive treatment is the future for better glycemic control in T1DM and that better automated insulin delivery systems will likely make adjunctive therapy unnecessary.
Dr. Nathan also observed “the rate of severe hypoglycemia in the whole sotagliflozin group was not significantly different from the rate in the placebo group,” and the risks and benefits of any adjunctive therapy for T1DM need to be carefully balanced.
While risks remain, one of the chairs of the session, Chantal Mathieu, MD, professor of medicine at the Katholieke Universiteit Leuven (Belgium), observed that “these are exciting times for all of us and hopefully for our patients.” She cautioned clinicians to remember, however, that “type 1 diabetes is a very different disease from type 2 diabetes, and so when we listen to [information about] all these adjunct[ive] therapies, when we read the papers, please interpret the data carefully.”
The trial was funded by Lexicon Pharmaceuticals. Sotagliflozin is being codeveloped with Sanofi. Dr. Davies disclosed acting as an advisor, consultant, or being a member of a speaker’s bureau for Sanofi-Aventis and several other companies. She was an investigator in the inTandem trials and her institution received funding from Lexicon to conduct the inTandem 2 and 3 clinical trials. Dr. Rosenstock disclosed research support and acting as an advisor to multiple pharmaceutical companies. Dr. Nathan had nothing to disclose. Dr. Mathieu chaired the session and did not present disclosures.
LISBON – Further phase 3 trial data show that the investigational dual sodium-glucose cotransporter 1 and 2 (SGLT1/2) inhibitor according to results reported at the annual meeting of the European Association for the Study of Diabetes.
In the inTandem3 trial, 28.6% of 699 people with T1DM treated with sotagliflozin on top of their usual insulin therapy achieved the primary composite endpoint, which was a glycated hemoglobin (HbA1c) level of 7% or lower at Week 24, with no episodes of severe hypoglycemia or diabetic ketoacidosis (DKA). In comparison, 15.2% of the 703 individuals who received a placebo in addition to their insulin therapy achieved this endpoint (P less than .001), according to Melanie J. Davies, MD, who presented the inTandem3 study results during a symposium on the sotagliflozin clinical program. The results were published online in the New England Journal of Medicine (2017 Sep 15. doi: 10.1056/NEJMoa1708337) to coincide with their presentation at the meeting.
However, the overall rate of DKA was higher in the patients treated with sotagliflozin than in those on placebo, at 3% versus 0.6%, respectively. DKA events most often occurred in persons using insulin pumps (4.4% vs. 9.7%) than in those taking insulin via multiple daily injections (2.1% vs 0.5%). Furthermore, in a post-hoc analysis, it was found that the rate of at least one episode of DKA was significantly higher in sotagliflozin- than placebo-treated patients who failed to reach the HbA1c target of below 7% (P less than .003), reported Dr. Davies.
The study findings “build on data seen inTandem 1 and inTandem 2 but in a more pragmatic design,” said study investigator Melanie Davies, MD, professor of diabetes medicine at the University of Leicester (England).
The inTandem studies
Dr. Davies observed that the sotagliflozin clinical trials program in persons with T1DM involved three phase 2 and three phase 3 studies. The latter, inTandem1, inTandem2, and inTandem3, were all 24-week trials, but there were some differences in the design.
inTandem1 and inTandem2 were the pivotal studies, one conducted in 793 patients in North America and the other in 782 patients in Europe and Israel. After a 2-week screening period, participants underwent a 6-week insulin optimization program before they were randomized to one of two doses of sotagliflozin (200 mg or 400 mg) or placebo for 24 weeks, with follow-up out to 52 weeks. The primary endpoint of these studies was the reduction in HbA1c versus placebo at 24 weeks.
By comparison, inTandem3 was a global study involving 1,405 individuals with T1DM who did not undergo the 6-week insulin optimization period. Instead there was a 2-week run-in period after the initial screening, and the study ran for only 24 weeks. Only one dose (400 mg) of sotagliflozin was used and the primary endpoint was a composite to try to see what the net clinical benefit would be, Dr. Davies explained.
The results of inTandem1 and inTandem2 were reported earlier this year at the American Diabetes Association Scientific Sessions, Dr. Davies noted, and sotagliflozin had “a good efficacy and safety profile as an adjunct to insulin in type 1 diabetes.”
The quest for adjunctive treatment
“For years we’ve been looking for adjunctive therapy for people with type 1 diabetes,” said Julio Rosenstock, MD, at the EASD meeting. Dr. Rosenstock, who is the director of the Dallas Diabetes Research Center at Medical City and involved in the sotagliflozin clinical trials program, noted that the quest for an adjunctive treatment was because “glucose control in type 1 diabetes remains tough and costly, despite multiple advances in insulin therapy, delivery systems, and monitoring methods over the years.”
Several approaches to adjunctive treatment had been proposed, but so far all with limited value, Dr. Rosenstock maintained. Despite no evidence for a benefit of adding metformin, for example, registry data suggest that up to 5% of people with T1DM are using it.
The recent findings of the REMOVAL trial showed metformin did not help change the HbA1c over time and there was no change in the primary outcome, he observed but a small improvement in a tertiary endpoint. “I can’t think of a more negative cardiovascular outcomes trial,” Dr. Rosenstock asserted. “There is not enough justification to use metformin in type 1 diabetes.”
By contrast there is a strong rationale for using SGLT inhibition, partly as the glucose-lowering effects are independent of insulin’s activity. Through inhibition of SGLT1, sotagliflozin reduces glucose absorption in the proximal intestine, thus blunting or delaying rising postprandial glucose levels. By also targeting SGLT2, sotagliflozin can reduce glucose resorption by the kidneys.
Risks and clinical implications
In an editorial accompanying the published findings, David Nathan, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, is not convinced that using adjunctive treatment is the future for better glycemic control in T1DM and that better automated insulin delivery systems will likely make adjunctive therapy unnecessary.
Dr. Nathan also observed “the rate of severe hypoglycemia in the whole sotagliflozin group was not significantly different from the rate in the placebo group,” and the risks and benefits of any adjunctive therapy for T1DM need to be carefully balanced.
While risks remain, one of the chairs of the session, Chantal Mathieu, MD, professor of medicine at the Katholieke Universiteit Leuven (Belgium), observed that “these are exciting times for all of us and hopefully for our patients.” She cautioned clinicians to remember, however, that “type 1 diabetes is a very different disease from type 2 diabetes, and so when we listen to [information about] all these adjunct[ive] therapies, when we read the papers, please interpret the data carefully.”
The trial was funded by Lexicon Pharmaceuticals. Sotagliflozin is being codeveloped with Sanofi. Dr. Davies disclosed acting as an advisor, consultant, or being a member of a speaker’s bureau for Sanofi-Aventis and several other companies. She was an investigator in the inTandem trials and her institution received funding from Lexicon to conduct the inTandem 2 and 3 clinical trials. Dr. Rosenstock disclosed research support and acting as an advisor to multiple pharmaceutical companies. Dr. Nathan had nothing to disclose. Dr. Mathieu chaired the session and did not present disclosures.
LISBON – Further phase 3 trial data show that the investigational dual sodium-glucose cotransporter 1 and 2 (SGLT1/2) inhibitor according to results reported at the annual meeting of the European Association for the Study of Diabetes.
In the inTandem3 trial, 28.6% of 699 people with T1DM treated with sotagliflozin on top of their usual insulin therapy achieved the primary composite endpoint, which was a glycated hemoglobin (HbA1c) level of 7% or lower at Week 24, with no episodes of severe hypoglycemia or diabetic ketoacidosis (DKA). In comparison, 15.2% of the 703 individuals who received a placebo in addition to their insulin therapy achieved this endpoint (P less than .001), according to Melanie J. Davies, MD, who presented the inTandem3 study results during a symposium on the sotagliflozin clinical program. The results were published online in the New England Journal of Medicine (2017 Sep 15. doi: 10.1056/NEJMoa1708337) to coincide with their presentation at the meeting.
However, the overall rate of DKA was higher in the patients treated with sotagliflozin than in those on placebo, at 3% versus 0.6%, respectively. DKA events most often occurred in persons using insulin pumps (4.4% vs. 9.7%) than in those taking insulin via multiple daily injections (2.1% vs 0.5%). Furthermore, in a post-hoc analysis, it was found that the rate of at least one episode of DKA was significantly higher in sotagliflozin- than placebo-treated patients who failed to reach the HbA1c target of below 7% (P less than .003), reported Dr. Davies.
The study findings “build on data seen inTandem 1 and inTandem 2 but in a more pragmatic design,” said study investigator Melanie Davies, MD, professor of diabetes medicine at the University of Leicester (England).
The inTandem studies
Dr. Davies observed that the sotagliflozin clinical trials program in persons with T1DM involved three phase 2 and three phase 3 studies. The latter, inTandem1, inTandem2, and inTandem3, were all 24-week trials, but there were some differences in the design.
inTandem1 and inTandem2 were the pivotal studies, one conducted in 793 patients in North America and the other in 782 patients in Europe and Israel. After a 2-week screening period, participants underwent a 6-week insulin optimization program before they were randomized to one of two doses of sotagliflozin (200 mg or 400 mg) or placebo for 24 weeks, with follow-up out to 52 weeks. The primary endpoint of these studies was the reduction in HbA1c versus placebo at 24 weeks.
By comparison, inTandem3 was a global study involving 1,405 individuals with T1DM who did not undergo the 6-week insulin optimization period. Instead there was a 2-week run-in period after the initial screening, and the study ran for only 24 weeks. Only one dose (400 mg) of sotagliflozin was used and the primary endpoint was a composite to try to see what the net clinical benefit would be, Dr. Davies explained.
The results of inTandem1 and inTandem2 were reported earlier this year at the American Diabetes Association Scientific Sessions, Dr. Davies noted, and sotagliflozin had “a good efficacy and safety profile as an adjunct to insulin in type 1 diabetes.”
The quest for adjunctive treatment
“For years we’ve been looking for adjunctive therapy for people with type 1 diabetes,” said Julio Rosenstock, MD, at the EASD meeting. Dr. Rosenstock, who is the director of the Dallas Diabetes Research Center at Medical City and involved in the sotagliflozin clinical trials program, noted that the quest for an adjunctive treatment was because “glucose control in type 1 diabetes remains tough and costly, despite multiple advances in insulin therapy, delivery systems, and monitoring methods over the years.”
Several approaches to adjunctive treatment had been proposed, but so far all with limited value, Dr. Rosenstock maintained. Despite no evidence for a benefit of adding metformin, for example, registry data suggest that up to 5% of people with T1DM are using it.
The recent findings of the REMOVAL trial showed metformin did not help change the HbA1c over time and there was no change in the primary outcome, he observed but a small improvement in a tertiary endpoint. “I can’t think of a more negative cardiovascular outcomes trial,” Dr. Rosenstock asserted. “There is not enough justification to use metformin in type 1 diabetes.”
By contrast there is a strong rationale for using SGLT inhibition, partly as the glucose-lowering effects are independent of insulin’s activity. Through inhibition of SGLT1, sotagliflozin reduces glucose absorption in the proximal intestine, thus blunting or delaying rising postprandial glucose levels. By also targeting SGLT2, sotagliflozin can reduce glucose resorption by the kidneys.
Risks and clinical implications
In an editorial accompanying the published findings, David Nathan, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, is not convinced that using adjunctive treatment is the future for better glycemic control in T1DM and that better automated insulin delivery systems will likely make adjunctive therapy unnecessary.
Dr. Nathan also observed “the rate of severe hypoglycemia in the whole sotagliflozin group was not significantly different from the rate in the placebo group,” and the risks and benefits of any adjunctive therapy for T1DM need to be carefully balanced.
While risks remain, one of the chairs of the session, Chantal Mathieu, MD, professor of medicine at the Katholieke Universiteit Leuven (Belgium), observed that “these are exciting times for all of us and hopefully for our patients.” She cautioned clinicians to remember, however, that “type 1 diabetes is a very different disease from type 2 diabetes, and so when we listen to [information about] all these adjunct[ive] therapies, when we read the papers, please interpret the data carefully.”
The trial was funded by Lexicon Pharmaceuticals. Sotagliflozin is being codeveloped with Sanofi. Dr. Davies disclosed acting as an advisor, consultant, or being a member of a speaker’s bureau for Sanofi-Aventis and several other companies. She was an investigator in the inTandem trials and her institution received funding from Lexicon to conduct the inTandem 2 and 3 clinical trials. Dr. Rosenstock disclosed research support and acting as an advisor to multiple pharmaceutical companies. Dr. Nathan had nothing to disclose. Dr. Mathieu chaired the session and did not present disclosures.
AT EASD 2017
Key clinical point: A higher proportion of people with type 1 diabetes mellitus (T1DM) treated with sotagliflozin than placebo achieved the primary composite endpoint, but there is the risk of diabetic ketoacidosis (DKA) in some.
Major finding: 28.6% versus 15.2% of sotaglifozin- and placebo-treated individuals achieved an HbA1c less than 7% at week 24, with no episodes of severe hypoglycemia or DKA (P less than .001).
Data source: The phase 3, randomized, controlled, multicenter inTandem3 trial in 1,402 people with type 1 diabetes on stable insulin therapy but with poor glycemic control.
Disclosures: The trial was funded by Lexicon Pharmaceuticals. Sotagliflozin is being codeveloped with Sanofi. Two presenters have received research support to perform clinical studies. The commentators had nothing to disclose.
SGLT inhibition back on track in phase 3 type T1DM trial
LISBON – Despite some earlier concerns over safety, sodium-glucose cotransporter (SGLT) inhibitors appear to be back on track for adjunctive use in people with type 1 diabetes (T1DM), according to phase 3 study findings presented at the annual meeting of the European Association for the Study of Diabetes.
Results of the DEPICT-1 study, showed improved glycemic control, greater weight loss, and no increased risk for either hypoglycemia or ketoacidosis in people treated with the SGLT2 inhibitor dapagliflozin (Farxiga) versus those treated with placebo.
When researchers compared the two dapagliflozin doses with placebo, the mean difference in body weight from baseline to week 24 was –2.96% and –3.72% (both P less than .0001).
Rates of any hypoglycemia in the placebo, 5-mg dapagliflozin, and 10-mg dapagliflozin groups were a respective 79.6%, 79.4%, and 79.4%, and rates of severe hypoglycemia were 7.3%, 7.6%, and 6.4%.
Diabetic ketoacidosis occurred in a respective 1.2%, 1.4%, and 1.7% of patients treated with placebo, dapagliflozin 5 mg, and dapagliflozin 10 mg, respectively.
“Based on this 24-week study, dapagliflozin may be considered as a good candidate as an adjunct to insulin to improve glycemic control in type 1 diabetes,” said the lead investigator for the DEPICT-1 trial, Paresh Dandona, MD, PhD, at the EASD 2017 meeting.
“There may also be other potential long-term cardiovascular and renal benefits, which have recently been demonstrated in type 2 diabetes,” suggested Dr. Dandona, who is a distinguished professor of medicine and chief of the division of endocrinology at the State University of New York at Buffalo. “Of course, that’s an open question, which needs to be investigated and determined in future.”
DEPICT-1 is the first phase 3, randomized, blinded, clinical trial of a selective SGLT2 inhibitor in T1DM, the study’s investigators said in an early online publication (Lancet Diabetes Endocrinol. 2017 Sep 13. doi: 10.1016/S2213-8587[17]30308-X). The study was conducted at 143 sites in 17 centers and involved 833 people with T1DM who were not achieving optimal blood glucose control.
Adults with an HbA1c of 7.7% or higher who had been taking insulin for at least 12 months were recruited and underwent an 8-week lead-in period to optimize their diabetes management before being randomized to take placebo or dapagliflozin 5 mg or 10 mg for 52 weeks. The primary endpoint was the change in HbA1c at Week 24.
DEPICT-1 “provides encouraging short-term data for the efficacy of adjunct SGLT2 inhibition in type 1 diabetes but might also provide insights into how the risk of ketoacidosis can be minimized,” John Petrie, MD, commented in an editorial that accompanied the published findings.
Dr. Petrie, professor of diabetic medicine at the Institute of Cardiovascular and Medical Sciences at the University of Glasgow, observed, however, that the results needed to be considered in the context of similar, and also recently presented, findings from the inTandem3 trial (N Engl J Med. 2017 Sep 13. doi: 10.1056/NEJMoa1708337) with the investigational dual SGLT1/SGLT2 inhibitor sotagliflozin. Other trials are expected to report soon with another SGLT2 inhibitor, empagliflozin.
In inTandem3, sotagliflozin helped more people who had T1DM and were on stable insulin to achieve an HbA1c level of 7% or lower at week 24 with no episodes of severe hypoglycemia or diabetic ketoacidosis, compared with those who took insulin alone (28.6% vs. 15.2%; P less than .001). However, the overall rates of ketoacidosis were higher in the patients treated with sotagliflozin than in those treated with placebo, at 3% versus 0.6%, respectively.
In both inTandem3 and DEPICT-1, strategies were in place to help carefully monitor and manage ketoacidosis. Dr. Petrie observed that patients in the latter trial were given a meter that measured both their blood glucose and ketones and were seen in a clinic regularly to assess the risk of ketoacidosis. These frequent visits, which occurred every 2 weeks, were shown to have an independent effect on HbA1c, he pointed out.
“Nevertheless, the investigators kept real-world clinical practice in mind by providing a very simple rule that insulin doses should be reduced by no more than 20% when study medication was started and that they should subsequently be titrated back towards the initial dose,” Dr. Petrie said. “This rule seemed to be quite effective in mitigating ketoacidosis and is feasible to implement in modern clinical practice since meters that measure ketones are increasingly available.
So does this mean a license for SGLT-targeting agents in T1DM could be coming soon? Not yet, Dr. Petrie suggests. “Regulators are likely to await at least the results of the 12-month follow-up, and data from other ongoing trials, before considering an indication for SGLT2 inhibitors in type 1 diabetes,” he said.
Adjunct treatment with these drugs also may require that individuals have “a good understanding of the early-warning symptoms of ketoacidosis” and be prepared to undertake regular home monitoring of both their blood glucose and ketones, as well as having a high level of communication with their diabetes health care providers.
AstraZeneca and Bristol-Myers Squibb funded the study.
Dr. Dandona received research support from AstraZeneca, Novo Nordisk, Boehringer Ingelheim, and AbbVie and was a consultant to AstraZeneca, Novo Nordisk, Sanofi-Aventis, and others.
Dr. Petrie disclosed receiving personal fees and travel expenses from Novo Nordisk; grants and personal fees from Sanofi-Aventis, Quintiles, and Janssen; nonfinancial support from Merck and Itamar Medical; and personal fees from Lilly, ACI Clinical, and Pfizer.
LISBON – Despite some earlier concerns over safety, sodium-glucose cotransporter (SGLT) inhibitors appear to be back on track for adjunctive use in people with type 1 diabetes (T1DM), according to phase 3 study findings presented at the annual meeting of the European Association for the Study of Diabetes.
Results of the DEPICT-1 study, showed improved glycemic control, greater weight loss, and no increased risk for either hypoglycemia or ketoacidosis in people treated with the SGLT2 inhibitor dapagliflozin (Farxiga) versus those treated with placebo.
When researchers compared the two dapagliflozin doses with placebo, the mean difference in body weight from baseline to week 24 was –2.96% and –3.72% (both P less than .0001).
Rates of any hypoglycemia in the placebo, 5-mg dapagliflozin, and 10-mg dapagliflozin groups were a respective 79.6%, 79.4%, and 79.4%, and rates of severe hypoglycemia were 7.3%, 7.6%, and 6.4%.
Diabetic ketoacidosis occurred in a respective 1.2%, 1.4%, and 1.7% of patients treated with placebo, dapagliflozin 5 mg, and dapagliflozin 10 mg, respectively.
“Based on this 24-week study, dapagliflozin may be considered as a good candidate as an adjunct to insulin to improve glycemic control in type 1 diabetes,” said the lead investigator for the DEPICT-1 trial, Paresh Dandona, MD, PhD, at the EASD 2017 meeting.
“There may also be other potential long-term cardiovascular and renal benefits, which have recently been demonstrated in type 2 diabetes,” suggested Dr. Dandona, who is a distinguished professor of medicine and chief of the division of endocrinology at the State University of New York at Buffalo. “Of course, that’s an open question, which needs to be investigated and determined in future.”
DEPICT-1 is the first phase 3, randomized, blinded, clinical trial of a selective SGLT2 inhibitor in T1DM, the study’s investigators said in an early online publication (Lancet Diabetes Endocrinol. 2017 Sep 13. doi: 10.1016/S2213-8587[17]30308-X). The study was conducted at 143 sites in 17 centers and involved 833 people with T1DM who were not achieving optimal blood glucose control.
Adults with an HbA1c of 7.7% or higher who had been taking insulin for at least 12 months were recruited and underwent an 8-week lead-in period to optimize their diabetes management before being randomized to take placebo or dapagliflozin 5 mg or 10 mg for 52 weeks. The primary endpoint was the change in HbA1c at Week 24.
DEPICT-1 “provides encouraging short-term data for the efficacy of adjunct SGLT2 inhibition in type 1 diabetes but might also provide insights into how the risk of ketoacidosis can be minimized,” John Petrie, MD, commented in an editorial that accompanied the published findings.
Dr. Petrie, professor of diabetic medicine at the Institute of Cardiovascular and Medical Sciences at the University of Glasgow, observed, however, that the results needed to be considered in the context of similar, and also recently presented, findings from the inTandem3 trial (N Engl J Med. 2017 Sep 13. doi: 10.1056/NEJMoa1708337) with the investigational dual SGLT1/SGLT2 inhibitor sotagliflozin. Other trials are expected to report soon with another SGLT2 inhibitor, empagliflozin.
In inTandem3, sotagliflozin helped more people who had T1DM and were on stable insulin to achieve an HbA1c level of 7% or lower at week 24 with no episodes of severe hypoglycemia or diabetic ketoacidosis, compared with those who took insulin alone (28.6% vs. 15.2%; P less than .001). However, the overall rates of ketoacidosis were higher in the patients treated with sotagliflozin than in those treated with placebo, at 3% versus 0.6%, respectively.
In both inTandem3 and DEPICT-1, strategies were in place to help carefully monitor and manage ketoacidosis. Dr. Petrie observed that patients in the latter trial were given a meter that measured both their blood glucose and ketones and were seen in a clinic regularly to assess the risk of ketoacidosis. These frequent visits, which occurred every 2 weeks, were shown to have an independent effect on HbA1c, he pointed out.
“Nevertheless, the investigators kept real-world clinical practice in mind by providing a very simple rule that insulin doses should be reduced by no more than 20% when study medication was started and that they should subsequently be titrated back towards the initial dose,” Dr. Petrie said. “This rule seemed to be quite effective in mitigating ketoacidosis and is feasible to implement in modern clinical practice since meters that measure ketones are increasingly available.
So does this mean a license for SGLT-targeting agents in T1DM could be coming soon? Not yet, Dr. Petrie suggests. “Regulators are likely to await at least the results of the 12-month follow-up, and data from other ongoing trials, before considering an indication for SGLT2 inhibitors in type 1 diabetes,” he said.
Adjunct treatment with these drugs also may require that individuals have “a good understanding of the early-warning symptoms of ketoacidosis” and be prepared to undertake regular home monitoring of both their blood glucose and ketones, as well as having a high level of communication with their diabetes health care providers.
AstraZeneca and Bristol-Myers Squibb funded the study.
Dr. Dandona received research support from AstraZeneca, Novo Nordisk, Boehringer Ingelheim, and AbbVie and was a consultant to AstraZeneca, Novo Nordisk, Sanofi-Aventis, and others.
Dr. Petrie disclosed receiving personal fees and travel expenses from Novo Nordisk; grants and personal fees from Sanofi-Aventis, Quintiles, and Janssen; nonfinancial support from Merck and Itamar Medical; and personal fees from Lilly, ACI Clinical, and Pfizer.
LISBON – Despite some earlier concerns over safety, sodium-glucose cotransporter (SGLT) inhibitors appear to be back on track for adjunctive use in people with type 1 diabetes (T1DM), according to phase 3 study findings presented at the annual meeting of the European Association for the Study of Diabetes.
Results of the DEPICT-1 study, showed improved glycemic control, greater weight loss, and no increased risk for either hypoglycemia or ketoacidosis in people treated with the SGLT2 inhibitor dapagliflozin (Farxiga) versus those treated with placebo.
When researchers compared the two dapagliflozin doses with placebo, the mean difference in body weight from baseline to week 24 was –2.96% and –3.72% (both P less than .0001).
Rates of any hypoglycemia in the placebo, 5-mg dapagliflozin, and 10-mg dapagliflozin groups were a respective 79.6%, 79.4%, and 79.4%, and rates of severe hypoglycemia were 7.3%, 7.6%, and 6.4%.
Diabetic ketoacidosis occurred in a respective 1.2%, 1.4%, and 1.7% of patients treated with placebo, dapagliflozin 5 mg, and dapagliflozin 10 mg, respectively.
“Based on this 24-week study, dapagliflozin may be considered as a good candidate as an adjunct to insulin to improve glycemic control in type 1 diabetes,” said the lead investigator for the DEPICT-1 trial, Paresh Dandona, MD, PhD, at the EASD 2017 meeting.
“There may also be other potential long-term cardiovascular and renal benefits, which have recently been demonstrated in type 2 diabetes,” suggested Dr. Dandona, who is a distinguished professor of medicine and chief of the division of endocrinology at the State University of New York at Buffalo. “Of course, that’s an open question, which needs to be investigated and determined in future.”
DEPICT-1 is the first phase 3, randomized, blinded, clinical trial of a selective SGLT2 inhibitor in T1DM, the study’s investigators said in an early online publication (Lancet Diabetes Endocrinol. 2017 Sep 13. doi: 10.1016/S2213-8587[17]30308-X). The study was conducted at 143 sites in 17 centers and involved 833 people with T1DM who were not achieving optimal blood glucose control.
Adults with an HbA1c of 7.7% or higher who had been taking insulin for at least 12 months were recruited and underwent an 8-week lead-in period to optimize their diabetes management before being randomized to take placebo or dapagliflozin 5 mg or 10 mg for 52 weeks. The primary endpoint was the change in HbA1c at Week 24.
DEPICT-1 “provides encouraging short-term data for the efficacy of adjunct SGLT2 inhibition in type 1 diabetes but might also provide insights into how the risk of ketoacidosis can be minimized,” John Petrie, MD, commented in an editorial that accompanied the published findings.
Dr. Petrie, professor of diabetic medicine at the Institute of Cardiovascular and Medical Sciences at the University of Glasgow, observed, however, that the results needed to be considered in the context of similar, and also recently presented, findings from the inTandem3 trial (N Engl J Med. 2017 Sep 13. doi: 10.1056/NEJMoa1708337) with the investigational dual SGLT1/SGLT2 inhibitor sotagliflozin. Other trials are expected to report soon with another SGLT2 inhibitor, empagliflozin.
In inTandem3, sotagliflozin helped more people who had T1DM and were on stable insulin to achieve an HbA1c level of 7% or lower at week 24 with no episodes of severe hypoglycemia or diabetic ketoacidosis, compared with those who took insulin alone (28.6% vs. 15.2%; P less than .001). However, the overall rates of ketoacidosis were higher in the patients treated with sotagliflozin than in those treated with placebo, at 3% versus 0.6%, respectively.
In both inTandem3 and DEPICT-1, strategies were in place to help carefully monitor and manage ketoacidosis. Dr. Petrie observed that patients in the latter trial were given a meter that measured both their blood glucose and ketones and were seen in a clinic regularly to assess the risk of ketoacidosis. These frequent visits, which occurred every 2 weeks, were shown to have an independent effect on HbA1c, he pointed out.
“Nevertheless, the investigators kept real-world clinical practice in mind by providing a very simple rule that insulin doses should be reduced by no more than 20% when study medication was started and that they should subsequently be titrated back towards the initial dose,” Dr. Petrie said. “This rule seemed to be quite effective in mitigating ketoacidosis and is feasible to implement in modern clinical practice since meters that measure ketones are increasingly available.
So does this mean a license for SGLT-targeting agents in T1DM could be coming soon? Not yet, Dr. Petrie suggests. “Regulators are likely to await at least the results of the 12-month follow-up, and data from other ongoing trials, before considering an indication for SGLT2 inhibitors in type 1 diabetes,” he said.
Adjunct treatment with these drugs also may require that individuals have “a good understanding of the early-warning symptoms of ketoacidosis” and be prepared to undertake regular home monitoring of both their blood glucose and ketones, as well as having a high level of communication with their diabetes health care providers.
AstraZeneca and Bristol-Myers Squibb funded the study.
Dr. Dandona received research support from AstraZeneca, Novo Nordisk, Boehringer Ingelheim, and AbbVie and was a consultant to AstraZeneca, Novo Nordisk, Sanofi-Aventis, and others.
Dr. Petrie disclosed receiving personal fees and travel expenses from Novo Nordisk; grants and personal fees from Sanofi-Aventis, Quintiles, and Janssen; nonfinancial support from Merck and Itamar Medical; and personal fees from Lilly, ACI Clinical, and Pfizer.
AT EASD 2017
Key clinical point:
Major finding: Dapagliflozin 5 mg and 10 mg reduced HbA1c from Week 0 to Week 24 more (0.42% and 0.45%, respectively) than did placebo (both P less than .0001).
Data source: A phase 3 randomized, double-blind, parallel-controlled, multicenter trial conducted in 833 people with type 1 diabetes.
Disclosures: AstraZeneca and Bristol-Myers Squibb funded the study. Dr. Dandona disclosed acting as a consultant to AstraZeneca, Novo Nordisk, Sanofi-Aventis, Merck, Intarcia, and AbbVie, as well as receiving research support from AstraZeneca, Novo Nordisk, Boehringer Ingelheim, and AbbVie. Dr. Petrie disclosed receiving personal fees and travel expenses from Novo Nordisk; grants and personal fees from Sanofi-Aventis, Quintiles, and Janssen; nonfinancial support from Merck and Itamar Medical; and personal fees from Lilly, ACI Clinical, and Pfizer.
Vitality predicts T2DM major cardiovascular event risk
LISBON – according to the results of a primary care study.
Seldom feeling “full of pep” or not having “a lot of energy” was associated with an increased risk of a major cardiovascular event (MACE) in middle-aged (55-66 years) adults with T2DM, Marta Vergara, MD, reported at the annual meeting of the European Association for the Study of Diabetes.
“It’s well known that patients with type 2 diabetes have a high risk for developing cardiovascular disease, and it is the main cause of death,” said Dr. Vergara of Linköping (Sweden) University.
While several risk factors for cardiovascular disease are known and widely monitored for in clinical practice worldwide, including psychological aspects such as mental stress, ways to identify patients earlier are needed.
“We need more clinically useful and easy-to-manage measurement instruments,” Dr. Vergara said.
Using data from the ongoing Cardiovascular Risk Factors in Patients With Diabetes – a Prospective Study in Primary Care (CARDIPP), Dr. Vergara and colleagues identified two questions used in the 36-Item Short Form (SF-36) that might fit the bill:
- ”How much time during the past 4 weeks did you feel full of pep?”
- “How much time during the past 4 weeks did you have a lot of energy?”
Patients had answered these questions using a 6-point scale ranging from 1, all of the time, to 6 none of the time.
In addition to completing the full SF-36 at recruitment, all patients enrolled in CARDIPP underwent thorough assessment of baseline cardiovascular risk. This included asking about their duration of diabetes and smoking history, taking glycemic and anthropometric readings, and recording their systolic blood pressure. Pulse wave velocity was also used to assess patients’ carotid-femoral artery stiffness.
Over a follow-up period of 7 years, 59 (7.8%) of 761 men and women aged 55-66 years developed ischemic heart disease or had a stroke and needed hospital treatment or died.
“Our data support the use of questions about sense of vitality in order to add prognostic information about subsequent risk of MACE independently of traditional risk markers, such as diabetes duration, age, HbA1c, gender, smoking, systolic blood pressure, and carotid-femoral pulse wave velocity and sagittal abdominal diameter,” Dr. Vergara said.
“We suggest that not feeling full of pep and not having a lot of energy could be used as risk markers for MACE in patients with type 2 diabetes.” These are two easy questions that could be asked as part of the risk assessment process in primary care, she suggested. “Other questions from the SF-36, such as feeling tired or worn out, were not independent markers of MACE,” Dr. Vergara said.
She said she had no relevant financial disclosures.
LISBON – according to the results of a primary care study.
Seldom feeling “full of pep” or not having “a lot of energy” was associated with an increased risk of a major cardiovascular event (MACE) in middle-aged (55-66 years) adults with T2DM, Marta Vergara, MD, reported at the annual meeting of the European Association for the Study of Diabetes.
“It’s well known that patients with type 2 diabetes have a high risk for developing cardiovascular disease, and it is the main cause of death,” said Dr. Vergara of Linköping (Sweden) University.
While several risk factors for cardiovascular disease are known and widely monitored for in clinical practice worldwide, including psychological aspects such as mental stress, ways to identify patients earlier are needed.
“We need more clinically useful and easy-to-manage measurement instruments,” Dr. Vergara said.
Using data from the ongoing Cardiovascular Risk Factors in Patients With Diabetes – a Prospective Study in Primary Care (CARDIPP), Dr. Vergara and colleagues identified two questions used in the 36-Item Short Form (SF-36) that might fit the bill:
- ”How much time during the past 4 weeks did you feel full of pep?”
- “How much time during the past 4 weeks did you have a lot of energy?”
Patients had answered these questions using a 6-point scale ranging from 1, all of the time, to 6 none of the time.
In addition to completing the full SF-36 at recruitment, all patients enrolled in CARDIPP underwent thorough assessment of baseline cardiovascular risk. This included asking about their duration of diabetes and smoking history, taking glycemic and anthropometric readings, and recording their systolic blood pressure. Pulse wave velocity was also used to assess patients’ carotid-femoral artery stiffness.
Over a follow-up period of 7 years, 59 (7.8%) of 761 men and women aged 55-66 years developed ischemic heart disease or had a stroke and needed hospital treatment or died.
“Our data support the use of questions about sense of vitality in order to add prognostic information about subsequent risk of MACE independently of traditional risk markers, such as diabetes duration, age, HbA1c, gender, smoking, systolic blood pressure, and carotid-femoral pulse wave velocity and sagittal abdominal diameter,” Dr. Vergara said.
“We suggest that not feeling full of pep and not having a lot of energy could be used as risk markers for MACE in patients with type 2 diabetes.” These are two easy questions that could be asked as part of the risk assessment process in primary care, she suggested. “Other questions from the SF-36, such as feeling tired or worn out, were not independent markers of MACE,” Dr. Vergara said.
She said she had no relevant financial disclosures.
LISBON – according to the results of a primary care study.
Seldom feeling “full of pep” or not having “a lot of energy” was associated with an increased risk of a major cardiovascular event (MACE) in middle-aged (55-66 years) adults with T2DM, Marta Vergara, MD, reported at the annual meeting of the European Association for the Study of Diabetes.
“It’s well known that patients with type 2 diabetes have a high risk for developing cardiovascular disease, and it is the main cause of death,” said Dr. Vergara of Linköping (Sweden) University.
While several risk factors for cardiovascular disease are known and widely monitored for in clinical practice worldwide, including psychological aspects such as mental stress, ways to identify patients earlier are needed.
“We need more clinically useful and easy-to-manage measurement instruments,” Dr. Vergara said.
Using data from the ongoing Cardiovascular Risk Factors in Patients With Diabetes – a Prospective Study in Primary Care (CARDIPP), Dr. Vergara and colleagues identified two questions used in the 36-Item Short Form (SF-36) that might fit the bill:
- ”How much time during the past 4 weeks did you feel full of pep?”
- “How much time during the past 4 weeks did you have a lot of energy?”
Patients had answered these questions using a 6-point scale ranging from 1, all of the time, to 6 none of the time.
In addition to completing the full SF-36 at recruitment, all patients enrolled in CARDIPP underwent thorough assessment of baseline cardiovascular risk. This included asking about their duration of diabetes and smoking history, taking glycemic and anthropometric readings, and recording their systolic blood pressure. Pulse wave velocity was also used to assess patients’ carotid-femoral artery stiffness.
Over a follow-up period of 7 years, 59 (7.8%) of 761 men and women aged 55-66 years developed ischemic heart disease or had a stroke and needed hospital treatment or died.
“Our data support the use of questions about sense of vitality in order to add prognostic information about subsequent risk of MACE independently of traditional risk markers, such as diabetes duration, age, HbA1c, gender, smoking, systolic blood pressure, and carotid-femoral pulse wave velocity and sagittal abdominal diameter,” Dr. Vergara said.
“We suggest that not feeling full of pep and not having a lot of energy could be used as risk markers for MACE in patients with type 2 diabetes.” These are two easy questions that could be asked as part of the risk assessment process in primary care, she suggested. “Other questions from the SF-36, such as feeling tired or worn out, were not independent markers of MACE,” Dr. Vergara said.
She said she had no relevant financial disclosures.
AT EASD 2017
Key clinical point: Two simple questions about vitality could help assess the risk of major cardiovascular events in patients with type 2 diabetes mellitus.
Major finding: The hazard ratios for seldom feeling “full of pep” and seldom having “lots of energy” and MACE were a respective 1.31 (P = .003) and 1.44 (P less than .0001).
Data source: A prospective, observational primary care study of 761 patients with type 2 diabetes mellitus.
Disclosures: The presenting author had no relevant financial disclosures.
Exercise reduces T1DM mortality risk
LISBON – Exercise was associated with a lower risk of all-cause mortality in patients with type 1 diabetes mellitus, regardless of whether or not they also had chronic kidney disease, according to an analysis of data from a large ongoing population study.
Fully adjusted hazard ratios comparing low versus moderate-to-high amounts of physical activity, intensity, frequency, and duration were a respective 1.63, 2.17, 2.07, and 1.86 in patients without CKD.
The corresponding HRs in patients with comorbid CKD were 1.47, 1.39, 1.90, and 1.49, although only the total exercise amount and frequency were statistically significant in this study group.
“So far, we know little about exercise and mortality in type 1 diabetes in a prospective setting,” Dr. Tikkanen-Dolenc added. There have been two large studies – the Pittsburgh Study (Diabetes. 1984;33:271-6) and the EURODIAB study (Diabetologia. 2013;56:82-91) – that have been conducted previously. The first showed a benefit of greater participation in team sports and leisure time physical activity (LTPA) in men only, and the second showed a borderline inverse association between a higher amount of LTPA and mortality in both sexes, she said. There are even fewer data specifically in patients with comorbid CKD, although exercise is recommended and appears to be safe, she said.
Dr. Tikkanen-Dolenc and her associates have previously shown that diabetic nephropathy largely accounts for the increased mortality risk in T1DM (Diabetes. 2009;58:1651-8), and that the intensity of exercise rather than the total amount could be important (Diabetologia. 2015;58:929-36). They have also found that high intensity and frequency of LTPA was associated with a decreased risk of cardiovascular events in patients with T1DM (Diabetologia. 2017;60:574-80). Now, they wanted to look more specifically at how LTPA might be associated with mortality in T1DM and also do a separate investigation of what happens when there is concomitant loss of kidney function.
Patients included in the analysis were part of the Finnish Diabetic Nephropathy (FinnDiane) Study, which is a nationwide study being conducted in 90 centers in Finland to look for risk factors and mechanisms behind diabetic complications. To date, the study involves around 5,000 participants, and 2,369 were included in the present analysis. Of these, 310 also had CKD, which was defined by an estimated glomerular filtration rate of 60 mL/min per 1.73 m2 or lower.
A previously validated questionnaire was used to measure LTPA. The total LTPA was calculated by measuring the time spent doing an activity by the intensity index expressed in metabolic equivalents (MET). The latter is a widely used unit in exercise research, Dr. Tikkanen-Dolenc said, and gives a measure of the ratio of the metabolic rate during activity to the rate at rest.
Over a follow-up of 11 years, 270 patients died and 2,099 were alive. Patients who died were significantly (P less than .001) older (50 vs. 38 years), had a longer duration of diabetes (33 vs. 22 years), higher systolic blood pressure (146 vs. 134 mm Hg), lower high-density lipoprotein cholesterol (1.38 vs. 1.44 mmol/L), and higher triglycerides (1.25 vs. 0.96 mmol/L). They were also more sedentary, with baseline LTPAs of 8.6 versus 17.2 MET/h (P less than .001). These factors were taken into account while analyzing the data in multiple ways for static and dynamic risk factors.
“These are great data, and this is one of the best clinical studies at the meeting,” observed Viktor Jörgens, MD, former executive director of the EASD and of the European Foundation for the Study of Diabetes, during the post-presentation discussion.
Dr. Jörgens suggested, however, that there was perhaps one important caveat before doctors around the globe started encouraging their patients to exercise more: the level of patient education around the risk for severe hypoglycemia with increasing exercise and routine availability of blood glucose monitoring.
“The problem with severe exercise in type 1 is severe hypoglycemia, and I know Finland is one of the leading countries for patient education and intensified insulin therapy,” Dr. Jörgens cautioned. “Therefore I assume that most of your patients were well educated on blood glucose monitoring, and knew everything about exercise and reducing the dosage [of insulin therapy].” Not all countries may have such high levels of patient education of monitoring, he suggested.
Dr. Tikkanen-Dolenc responded that “of course patient education is needed, such as on continuous glucose monitoring, and there is a risk, but when we look to current recommendations, we still do recommend exercise, even in type 1 diabetes, and it appears to be safe, but that’s a good point and that’s something we need to note.”
Neither Dr. Tikkanen-Dolenc or Dr. Jörgens had anything to disclose.
LISBON – Exercise was associated with a lower risk of all-cause mortality in patients with type 1 diabetes mellitus, regardless of whether or not they also had chronic kidney disease, according to an analysis of data from a large ongoing population study.
Fully adjusted hazard ratios comparing low versus moderate-to-high amounts of physical activity, intensity, frequency, and duration were a respective 1.63, 2.17, 2.07, and 1.86 in patients without CKD.
The corresponding HRs in patients with comorbid CKD were 1.47, 1.39, 1.90, and 1.49, although only the total exercise amount and frequency were statistically significant in this study group.
“So far, we know little about exercise and mortality in type 1 diabetes in a prospective setting,” Dr. Tikkanen-Dolenc added. There have been two large studies – the Pittsburgh Study (Diabetes. 1984;33:271-6) and the EURODIAB study (Diabetologia. 2013;56:82-91) – that have been conducted previously. The first showed a benefit of greater participation in team sports and leisure time physical activity (LTPA) in men only, and the second showed a borderline inverse association between a higher amount of LTPA and mortality in both sexes, she said. There are even fewer data specifically in patients with comorbid CKD, although exercise is recommended and appears to be safe, she said.
Dr. Tikkanen-Dolenc and her associates have previously shown that diabetic nephropathy largely accounts for the increased mortality risk in T1DM (Diabetes. 2009;58:1651-8), and that the intensity of exercise rather than the total amount could be important (Diabetologia. 2015;58:929-36). They have also found that high intensity and frequency of LTPA was associated with a decreased risk of cardiovascular events in patients with T1DM (Diabetologia. 2017;60:574-80). Now, they wanted to look more specifically at how LTPA might be associated with mortality in T1DM and also do a separate investigation of what happens when there is concomitant loss of kidney function.
Patients included in the analysis were part of the Finnish Diabetic Nephropathy (FinnDiane) Study, which is a nationwide study being conducted in 90 centers in Finland to look for risk factors and mechanisms behind diabetic complications. To date, the study involves around 5,000 participants, and 2,369 were included in the present analysis. Of these, 310 also had CKD, which was defined by an estimated glomerular filtration rate of 60 mL/min per 1.73 m2 or lower.
A previously validated questionnaire was used to measure LTPA. The total LTPA was calculated by measuring the time spent doing an activity by the intensity index expressed in metabolic equivalents (MET). The latter is a widely used unit in exercise research, Dr. Tikkanen-Dolenc said, and gives a measure of the ratio of the metabolic rate during activity to the rate at rest.
Over a follow-up of 11 years, 270 patients died and 2,099 were alive. Patients who died were significantly (P less than .001) older (50 vs. 38 years), had a longer duration of diabetes (33 vs. 22 years), higher systolic blood pressure (146 vs. 134 mm Hg), lower high-density lipoprotein cholesterol (1.38 vs. 1.44 mmol/L), and higher triglycerides (1.25 vs. 0.96 mmol/L). They were also more sedentary, with baseline LTPAs of 8.6 versus 17.2 MET/h (P less than .001). These factors were taken into account while analyzing the data in multiple ways for static and dynamic risk factors.
“These are great data, and this is one of the best clinical studies at the meeting,” observed Viktor Jörgens, MD, former executive director of the EASD and of the European Foundation for the Study of Diabetes, during the post-presentation discussion.
Dr. Jörgens suggested, however, that there was perhaps one important caveat before doctors around the globe started encouraging their patients to exercise more: the level of patient education around the risk for severe hypoglycemia with increasing exercise and routine availability of blood glucose monitoring.
“The problem with severe exercise in type 1 is severe hypoglycemia, and I know Finland is one of the leading countries for patient education and intensified insulin therapy,” Dr. Jörgens cautioned. “Therefore I assume that most of your patients were well educated on blood glucose monitoring, and knew everything about exercise and reducing the dosage [of insulin therapy].” Not all countries may have such high levels of patient education of monitoring, he suggested.
Dr. Tikkanen-Dolenc responded that “of course patient education is needed, such as on continuous glucose monitoring, and there is a risk, but when we look to current recommendations, we still do recommend exercise, even in type 1 diabetes, and it appears to be safe, but that’s a good point and that’s something we need to note.”
Neither Dr. Tikkanen-Dolenc or Dr. Jörgens had anything to disclose.
LISBON – Exercise was associated with a lower risk of all-cause mortality in patients with type 1 diabetes mellitus, regardless of whether or not they also had chronic kidney disease, according to an analysis of data from a large ongoing population study.
Fully adjusted hazard ratios comparing low versus moderate-to-high amounts of physical activity, intensity, frequency, and duration were a respective 1.63, 2.17, 2.07, and 1.86 in patients without CKD.
The corresponding HRs in patients with comorbid CKD were 1.47, 1.39, 1.90, and 1.49, although only the total exercise amount and frequency were statistically significant in this study group.
“So far, we know little about exercise and mortality in type 1 diabetes in a prospective setting,” Dr. Tikkanen-Dolenc added. There have been two large studies – the Pittsburgh Study (Diabetes. 1984;33:271-6) and the EURODIAB study (Diabetologia. 2013;56:82-91) – that have been conducted previously. The first showed a benefit of greater participation in team sports and leisure time physical activity (LTPA) in men only, and the second showed a borderline inverse association between a higher amount of LTPA and mortality in both sexes, she said. There are even fewer data specifically in patients with comorbid CKD, although exercise is recommended and appears to be safe, she said.
Dr. Tikkanen-Dolenc and her associates have previously shown that diabetic nephropathy largely accounts for the increased mortality risk in T1DM (Diabetes. 2009;58:1651-8), and that the intensity of exercise rather than the total amount could be important (Diabetologia. 2015;58:929-36). They have also found that high intensity and frequency of LTPA was associated with a decreased risk of cardiovascular events in patients with T1DM (Diabetologia. 2017;60:574-80). Now, they wanted to look more specifically at how LTPA might be associated with mortality in T1DM and also do a separate investigation of what happens when there is concomitant loss of kidney function.
Patients included in the analysis were part of the Finnish Diabetic Nephropathy (FinnDiane) Study, which is a nationwide study being conducted in 90 centers in Finland to look for risk factors and mechanisms behind diabetic complications. To date, the study involves around 5,000 participants, and 2,369 were included in the present analysis. Of these, 310 also had CKD, which was defined by an estimated glomerular filtration rate of 60 mL/min per 1.73 m2 or lower.
A previously validated questionnaire was used to measure LTPA. The total LTPA was calculated by measuring the time spent doing an activity by the intensity index expressed in metabolic equivalents (MET). The latter is a widely used unit in exercise research, Dr. Tikkanen-Dolenc said, and gives a measure of the ratio of the metabolic rate during activity to the rate at rest.
Over a follow-up of 11 years, 270 patients died and 2,099 were alive. Patients who died were significantly (P less than .001) older (50 vs. 38 years), had a longer duration of diabetes (33 vs. 22 years), higher systolic blood pressure (146 vs. 134 mm Hg), lower high-density lipoprotein cholesterol (1.38 vs. 1.44 mmol/L), and higher triglycerides (1.25 vs. 0.96 mmol/L). They were also more sedentary, with baseline LTPAs of 8.6 versus 17.2 MET/h (P less than .001). These factors were taken into account while analyzing the data in multiple ways for static and dynamic risk factors.
“These are great data, and this is one of the best clinical studies at the meeting,” observed Viktor Jörgens, MD, former executive director of the EASD and of the European Foundation for the Study of Diabetes, during the post-presentation discussion.
Dr. Jörgens suggested, however, that there was perhaps one important caveat before doctors around the globe started encouraging their patients to exercise more: the level of patient education around the risk for severe hypoglycemia with increasing exercise and routine availability of blood glucose monitoring.
“The problem with severe exercise in type 1 is severe hypoglycemia, and I know Finland is one of the leading countries for patient education and intensified insulin therapy,” Dr. Jörgens cautioned. “Therefore I assume that most of your patients were well educated on blood glucose monitoring, and knew everything about exercise and reducing the dosage [of insulin therapy].” Not all countries may have such high levels of patient education of monitoring, he suggested.
Dr. Tikkanen-Dolenc responded that “of course patient education is needed, such as on continuous glucose monitoring, and there is a risk, but when we look to current recommendations, we still do recommend exercise, even in type 1 diabetes, and it appears to be safe, but that’s a good point and that’s something we need to note.”
Neither Dr. Tikkanen-Dolenc or Dr. Jörgens had anything to disclose.
AT EASD 2017
Key clinical point: Exercise was associated with a lower risk of all-cause mortality in patients with type 1 diabetes mellitus, even in those with chronic kidney disease.
Major finding: Increasing exercise intensity and frequency was inversely associated with increased mortality in patients with T1DM and CKD (hazard ratios, 1.47 and 1.90, respectively).
Data source: The Finnish Diabetic Nephropathy Study; 2,369 patients with T1DM were included in the analyses.
Disclosures: The presenting author and commentator had no disclosures.
Triple therapy for type 2 diabetes goes beyond glucose control
LISBON – Greater glycemic control and weight reductions were achieved by people with poorly controlled type 2 diabetes who used a fixed dual combination of a sodium-glucose cotransporter-2 (SGLT2) inhibitor and dipeptidyl peptidase 4 (DPP-4) inhibitor added to metformin compared with those who used a DPP-4 inhibitor plus metformin in a phase 3b study.
The addition of dapagliflozin/saxagliptin (Qtern, AstraZeneca) to metformin (DAPA/SAXA-MET) resulted in a 1.4% decrease in glycated hemoglobin A1c (HbA1c) from baseline to week 26, which was 0.3% more than the 1.1% drop seen when sitagliptin (Januvia, Merck) was added onto metformin (SITA-MET; P less than .008).
“With the triple therapy there was a more profound reduction in glycated hemoglobin,” Stefano Del Prato, MD, professor of endocrinology and metabolism and chief of the section of diabetes at the University of Pisa, Italy, reported at the annual meeting of the European Association for the Study of Diabetes. “Triple therapy was also associated with significant reductions in fasting plasma glucose and body weight versus sitagliptin added on to metformin,” he said.
Of note, a higher percentage of patients given the triple therapy achieved a target HbA1c of less than 7% compared with those receiving the dual therapy (37% vs. 25%; P = .0034) at 26 weeks, and fasting plasma glucose also fell to a greater extent (–32 mg/dL vs. –11 mg/dL; P less than .0001).
“This study beautifully illustrates to me that when we use SGLT2 inhibitors we shouldn’t be just fixated by the glycemic difference,” Naveed Sattar, MD, professor of cardiovascular and medical sciences at the University of Glasgow, Scotland, said from the audience.
Dr. Sattar, who was not involved in the study, suggested that the diabetes community was at the point of a new paradigm: “We could use these drugs to protect the kidneys and the heart,” he suggested. “As a diabetes community we should move beyond glycemia; it’s the other benefits that we should be thinking about when we prescribe these drugs,” he said.
Not everyone was as enthusiastic. One delegate said the study design was “screwy” because two different DPP-4 inhibitors were used. Dr. Del Prato responded, saying that the dual sitagliptin/metformin combination was the comparator arm because it was the most commonly used combination, and saxagliptin was used as it was available in a fixed combination with a DPP4 inhibitor, dapagliflozin.
“Current guidelines recommend addition of a single antidiabetes agent to metformin to achieve and maintain glycemic targets in patients with type 2 diabetes; however, responses to dual therapy are often limited and not persistent in time,” Dr. Del Prato observed. He added that there was already some evidence that triple drug combinations with complementary modes of action “provide increased efficacy for some patients” and that both SGLT2 inhibitors and DPP-4 inhibitors were recommended in combination with metformin.
The aim of the randomized, double-blind, double-dummy study he presented, therefore, was to compare the efficacy and safety of adding the combination of an SGLT2 (dapagliflozin) plus a DPP-4 inhibitor (saxagliptin) versus adding a DPP-4 inhibitor (sitagliptin) alone to metformin “across diverse predefined subpopulations of patients with inadequately controlled type 2 diabetes.”
Patients recruited into the trial had to have been taking a stable dose of metformin of more than 1,500 mg/day for at least 8 weeks at study entry, with a baseline HbA1c of 8%-10.5%, and a fasting plasma glucose of 270 mg/dL or less. Of 861 people screened, 461 were randomized, with 232 receiving daily treatment with the fixed combination of DAPA (10 mg) plus SAXA (5 mg) and 229 receiving sitagliptin (100 mg) added to their existing metformin regimen.
A higher rate of completion (92% vs. 86%) was seen with triple therapy than with the dual therapy, although reasons for discontinuation were similar between the groups. Both triple and dual therapy were “well tolerated,” Dr. Del Prato reported. The rates of any adverse event (AE), drug-related AEs, serious AEs, and drug-related serious AEs were a respective 48.7% vs. 47.6%, 7.2% vs. 6.6%, 2.2% vs. 3.9%, and 0% vs. 0.4%.
“No patient experienced a major episode of hypoglycemia,” Dr. Del Prato said, noting that 3.9% of the triple-therapy-treated versus 2.6% of the dual-therapy-treated subjects experienced this AE.
Urogenital infections were “infrequent” with a “similar incidence of genital infections” at 2.6% for the triple therapy group and 2.2% for the double therapy group. Urinary tract infections occurred “slightly more frequently” with the triple than dual regimen, at 4.7% vs. 2.2%, respectively.
“Improvements in glycated hemoglobin, with the addition of once-daily dapagliflozin and saxagliptin to metformin were greater than with the addition of sitagliptin alone on top of metformin and were achieved regardless of baseline A1c, age, gender, race, and region,” Dr. Del Prato said. Patients will continue to be followed in the trial for 1 year and results of this extension phase of the study will provide information on the durability of responses to DAPA/SAXA/MET versus SITA/MET.
AstraZeneca funded the study. Dr. Del Prato disclosed ties with AstraZeneca, Boehringer Ingelheim, Merck Sharpe & Dohme, Novartis, Eli Lilly, GlaxoSmithKline, Hanmi Pharmaceuticals, Intarcia Therapeutics, Janssen Pharmaceuticals, Novo Nordisk, Sanofi-Aventis, Servier, and Takeda Pharmaceuticals. Dr. Sattar disclosed ties with Amgen, Boehringer Ingelheim, Eli Lilly, Janssen, and Novo Nordisk.
LISBON – Greater glycemic control and weight reductions were achieved by people with poorly controlled type 2 diabetes who used a fixed dual combination of a sodium-glucose cotransporter-2 (SGLT2) inhibitor and dipeptidyl peptidase 4 (DPP-4) inhibitor added to metformin compared with those who used a DPP-4 inhibitor plus metformin in a phase 3b study.
The addition of dapagliflozin/saxagliptin (Qtern, AstraZeneca) to metformin (DAPA/SAXA-MET) resulted in a 1.4% decrease in glycated hemoglobin A1c (HbA1c) from baseline to week 26, which was 0.3% more than the 1.1% drop seen when sitagliptin (Januvia, Merck) was added onto metformin (SITA-MET; P less than .008).
“With the triple therapy there was a more profound reduction in glycated hemoglobin,” Stefano Del Prato, MD, professor of endocrinology and metabolism and chief of the section of diabetes at the University of Pisa, Italy, reported at the annual meeting of the European Association for the Study of Diabetes. “Triple therapy was also associated with significant reductions in fasting plasma glucose and body weight versus sitagliptin added on to metformin,” he said.
Of note, a higher percentage of patients given the triple therapy achieved a target HbA1c of less than 7% compared with those receiving the dual therapy (37% vs. 25%; P = .0034) at 26 weeks, and fasting plasma glucose also fell to a greater extent (–32 mg/dL vs. –11 mg/dL; P less than .0001).
“This study beautifully illustrates to me that when we use SGLT2 inhibitors we shouldn’t be just fixated by the glycemic difference,” Naveed Sattar, MD, professor of cardiovascular and medical sciences at the University of Glasgow, Scotland, said from the audience.
Dr. Sattar, who was not involved in the study, suggested that the diabetes community was at the point of a new paradigm: “We could use these drugs to protect the kidneys and the heart,” he suggested. “As a diabetes community we should move beyond glycemia; it’s the other benefits that we should be thinking about when we prescribe these drugs,” he said.
Not everyone was as enthusiastic. One delegate said the study design was “screwy” because two different DPP-4 inhibitors were used. Dr. Del Prato responded, saying that the dual sitagliptin/metformin combination was the comparator arm because it was the most commonly used combination, and saxagliptin was used as it was available in a fixed combination with a DPP4 inhibitor, dapagliflozin.
“Current guidelines recommend addition of a single antidiabetes agent to metformin to achieve and maintain glycemic targets in patients with type 2 diabetes; however, responses to dual therapy are often limited and not persistent in time,” Dr. Del Prato observed. He added that there was already some evidence that triple drug combinations with complementary modes of action “provide increased efficacy for some patients” and that both SGLT2 inhibitors and DPP-4 inhibitors were recommended in combination with metformin.
The aim of the randomized, double-blind, double-dummy study he presented, therefore, was to compare the efficacy and safety of adding the combination of an SGLT2 (dapagliflozin) plus a DPP-4 inhibitor (saxagliptin) versus adding a DPP-4 inhibitor (sitagliptin) alone to metformin “across diverse predefined subpopulations of patients with inadequately controlled type 2 diabetes.”
Patients recruited into the trial had to have been taking a stable dose of metformin of more than 1,500 mg/day for at least 8 weeks at study entry, with a baseline HbA1c of 8%-10.5%, and a fasting plasma glucose of 270 mg/dL or less. Of 861 people screened, 461 were randomized, with 232 receiving daily treatment with the fixed combination of DAPA (10 mg) plus SAXA (5 mg) and 229 receiving sitagliptin (100 mg) added to their existing metformin regimen.
A higher rate of completion (92% vs. 86%) was seen with triple therapy than with the dual therapy, although reasons for discontinuation were similar between the groups. Both triple and dual therapy were “well tolerated,” Dr. Del Prato reported. The rates of any adverse event (AE), drug-related AEs, serious AEs, and drug-related serious AEs were a respective 48.7% vs. 47.6%, 7.2% vs. 6.6%, 2.2% vs. 3.9%, and 0% vs. 0.4%.
“No patient experienced a major episode of hypoglycemia,” Dr. Del Prato said, noting that 3.9% of the triple-therapy-treated versus 2.6% of the dual-therapy-treated subjects experienced this AE.
Urogenital infections were “infrequent” with a “similar incidence of genital infections” at 2.6% for the triple therapy group and 2.2% for the double therapy group. Urinary tract infections occurred “slightly more frequently” with the triple than dual regimen, at 4.7% vs. 2.2%, respectively.
“Improvements in glycated hemoglobin, with the addition of once-daily dapagliflozin and saxagliptin to metformin were greater than with the addition of sitagliptin alone on top of metformin and were achieved regardless of baseline A1c, age, gender, race, and region,” Dr. Del Prato said. Patients will continue to be followed in the trial for 1 year and results of this extension phase of the study will provide information on the durability of responses to DAPA/SAXA/MET versus SITA/MET.
AstraZeneca funded the study. Dr. Del Prato disclosed ties with AstraZeneca, Boehringer Ingelheim, Merck Sharpe & Dohme, Novartis, Eli Lilly, GlaxoSmithKline, Hanmi Pharmaceuticals, Intarcia Therapeutics, Janssen Pharmaceuticals, Novo Nordisk, Sanofi-Aventis, Servier, and Takeda Pharmaceuticals. Dr. Sattar disclosed ties with Amgen, Boehringer Ingelheim, Eli Lilly, Janssen, and Novo Nordisk.
LISBON – Greater glycemic control and weight reductions were achieved by people with poorly controlled type 2 diabetes who used a fixed dual combination of a sodium-glucose cotransporter-2 (SGLT2) inhibitor and dipeptidyl peptidase 4 (DPP-4) inhibitor added to metformin compared with those who used a DPP-4 inhibitor plus metformin in a phase 3b study.
The addition of dapagliflozin/saxagliptin (Qtern, AstraZeneca) to metformin (DAPA/SAXA-MET) resulted in a 1.4% decrease in glycated hemoglobin A1c (HbA1c) from baseline to week 26, which was 0.3% more than the 1.1% drop seen when sitagliptin (Januvia, Merck) was added onto metformin (SITA-MET; P less than .008).
“With the triple therapy there was a more profound reduction in glycated hemoglobin,” Stefano Del Prato, MD, professor of endocrinology and metabolism and chief of the section of diabetes at the University of Pisa, Italy, reported at the annual meeting of the European Association for the Study of Diabetes. “Triple therapy was also associated with significant reductions in fasting plasma glucose and body weight versus sitagliptin added on to metformin,” he said.
Of note, a higher percentage of patients given the triple therapy achieved a target HbA1c of less than 7% compared with those receiving the dual therapy (37% vs. 25%; P = .0034) at 26 weeks, and fasting plasma glucose also fell to a greater extent (–32 mg/dL vs. –11 mg/dL; P less than .0001).
“This study beautifully illustrates to me that when we use SGLT2 inhibitors we shouldn’t be just fixated by the glycemic difference,” Naveed Sattar, MD, professor of cardiovascular and medical sciences at the University of Glasgow, Scotland, said from the audience.
Dr. Sattar, who was not involved in the study, suggested that the diabetes community was at the point of a new paradigm: “We could use these drugs to protect the kidneys and the heart,” he suggested. “As a diabetes community we should move beyond glycemia; it’s the other benefits that we should be thinking about when we prescribe these drugs,” he said.
Not everyone was as enthusiastic. One delegate said the study design was “screwy” because two different DPP-4 inhibitors were used. Dr. Del Prato responded, saying that the dual sitagliptin/metformin combination was the comparator arm because it was the most commonly used combination, and saxagliptin was used as it was available in a fixed combination with a DPP4 inhibitor, dapagliflozin.
“Current guidelines recommend addition of a single antidiabetes agent to metformin to achieve and maintain glycemic targets in patients with type 2 diabetes; however, responses to dual therapy are often limited and not persistent in time,” Dr. Del Prato observed. He added that there was already some evidence that triple drug combinations with complementary modes of action “provide increased efficacy for some patients” and that both SGLT2 inhibitors and DPP-4 inhibitors were recommended in combination with metformin.
The aim of the randomized, double-blind, double-dummy study he presented, therefore, was to compare the efficacy and safety of adding the combination of an SGLT2 (dapagliflozin) plus a DPP-4 inhibitor (saxagliptin) versus adding a DPP-4 inhibitor (sitagliptin) alone to metformin “across diverse predefined subpopulations of patients with inadequately controlled type 2 diabetes.”
Patients recruited into the trial had to have been taking a stable dose of metformin of more than 1,500 mg/day for at least 8 weeks at study entry, with a baseline HbA1c of 8%-10.5%, and a fasting plasma glucose of 270 mg/dL or less. Of 861 people screened, 461 were randomized, with 232 receiving daily treatment with the fixed combination of DAPA (10 mg) plus SAXA (5 mg) and 229 receiving sitagliptin (100 mg) added to their existing metformin regimen.
A higher rate of completion (92% vs. 86%) was seen with triple therapy than with the dual therapy, although reasons for discontinuation were similar between the groups. Both triple and dual therapy were “well tolerated,” Dr. Del Prato reported. The rates of any adverse event (AE), drug-related AEs, serious AEs, and drug-related serious AEs were a respective 48.7% vs. 47.6%, 7.2% vs. 6.6%, 2.2% vs. 3.9%, and 0% vs. 0.4%.
“No patient experienced a major episode of hypoglycemia,” Dr. Del Prato said, noting that 3.9% of the triple-therapy-treated versus 2.6% of the dual-therapy-treated subjects experienced this AE.
Urogenital infections were “infrequent” with a “similar incidence of genital infections” at 2.6% for the triple therapy group and 2.2% for the double therapy group. Urinary tract infections occurred “slightly more frequently” with the triple than dual regimen, at 4.7% vs. 2.2%, respectively.
“Improvements in glycated hemoglobin, with the addition of once-daily dapagliflozin and saxagliptin to metformin were greater than with the addition of sitagliptin alone on top of metformin and were achieved regardless of baseline A1c, age, gender, race, and region,” Dr. Del Prato said. Patients will continue to be followed in the trial for 1 year and results of this extension phase of the study will provide information on the durability of responses to DAPA/SAXA/MET versus SITA/MET.
AstraZeneca funded the study. Dr. Del Prato disclosed ties with AstraZeneca, Boehringer Ingelheim, Merck Sharpe & Dohme, Novartis, Eli Lilly, GlaxoSmithKline, Hanmi Pharmaceuticals, Intarcia Therapeutics, Janssen Pharmaceuticals, Novo Nordisk, Sanofi-Aventis, Servier, and Takeda Pharmaceuticals. Dr. Sattar disclosed ties with Amgen, Boehringer Ingelheim, Eli Lilly, Janssen, and Novo Nordisk.
AT EASD 2017
Key clinical point: A triple versus dual therapy approach resulted in greater glycemic control and weight reduction in people with type 2 diabetes.
Major finding: The addition of dapagliflozin/saxagliptin to metformin resulted in a 1.4% decrease in glycated hemoglobin A1c from baseline to week 26.
Data source: Multinational, active-controlled, double-blind, double-dummy, 26-week phase 3b trial of 461 patients with type 2 diabetes treated with dapagliflozin/saxagliptin or sitagliptin in addition to metformin.
Disclosures: AstraZeneca funded the study. Dr. Del Prato disclosed ties with AstraZeneca, Boehringer Ingelheim, Merck Sharpe & Dohme, Novartis, Eli Lilly, GlaxoSmithKline, Hanmi Pharmaceuticals, Intarcia Therapeutics, Janssen Pharmaceuticals, Novo Nordisk, Sanofi-Aventis, Servier, and Takeda Pharmaceuticals. Dr. Sattar disclosed ties with Amgen, Boehringer Ingelheim, Eli Lilly, Janssen, and Novo Nordisk.
Intensified approach reduces long-term heart failure risk in T2DM
LISBON – A 70% reduction in the risk of hospitalization for heart failure was achieved in people with type 2 diabetes mellitus (T2DM) given an intensified, multifactorial intervention versus conventional treatment in a long-term follow up of the STENO-2 study.
Over 21 years, 34 (21%) of 160 study subjects developed heart failure; 24 (30%) had initially been treated conventionally, and 10 (13%) had initially received intensive treatment. The annualized rates of heart failure were calculated as a respective 2.4% and 0.8% (hazard ratio, 0.30; P less than .002), Jens Øllgaard, PhD, reported at the annual meeting of the European Association for the Study of Diabetes.
Furthermore, after adjustment was made for subject age, gender, prohormone brain natriuretic peptide levels, and ejection fraction at recruitment, there was a 76% relative risk reduction in heart failure with the intensified strategy versus conventional treatment.
“Heart failure in diabetes is frequent, fatal, and at least until very recently, quite forgotten,” said Dr. Øllgaard, who presented the research performed while he was at the STENO Diabetes Center in Copenhagen.
Dr. Øllgaard, who now works for Novo Nordisk, noted that heart failure was four times more likely to occur in patients with T2DM who had microalbuminuria than in those with normal albumin levels in the urine, and the median survival was around 3.5 years. While there is no regulatory requirement at present to stipulate that heart failure should be assessed in trials looking at the cardiovascular safety of T2DM treatments, recording such information is something that the STENO-2 investigators would recommend.
STENO-2 was an open, parallel group study initiated in 1993 to compare conventional multifactorial treatment of T2DM with an intensified approach over an 8-year period. After the primary composite cardiovascular endpoint was assessed, the trial continued as an observational study, with all patients given the intensified, multifactorial treatment that consisted of lifestyle measures and medications targeting hyperglycemia, hypertension, hypercholesterolemia, and hypercoagulation.
The primary endpoint of the long-term follow-up study was the difference in median survival time between the original treatment groups with and without incident cardiovascular disease. The results showed a 48% relative reduction in the risk of death; those initially given the intensified treatment had an increased lifespan of 7.9 years and an 8.1-year increased survival without cardiovascular disease versus those who had initially received conventional treatment (Diabetologica 2016;59:2298-307).
Dr. Øllgaard presented data on heart failure outcomes obtained from a post-hoc analysis of prospectively collected and externally adjudicated patient records.
In addition to the reductions in the primary outcome of time to heart failure, the secondary outcomes of time to heart failure or cardiovascular mortality (HR, 0.38; P = .006) and heart failure or all-cause mortality (relative risk reduction, 49%; P = .001) also favored initial intensive treatment versus conventional treatment.
The number of patients who would need to be treated for 1 year to prevent one heart failure event was 63. The number needed to treat (NNT) to prevent heart failure or cardiovascular death was 48, and the NNT or heart failure or all-cause death was 37.
“Intensified, multifactorial intervention reduces the risk of heart failure and underlines the need for early, intensive treatment in these patients,” Dr. Øllgaard said. “Diabetologists should be aware of this increased risk and the early clinical signs and biomarkers of heart failure.” He added the study “also emphasizes the need for close collaboration, locally and globally, between endocrinologists and cardiologists.”
The STENO-2 long-term follow-up analysis was sponsored by an unrestricted grant from Novo Nordisk. Dr. Øllgaard disclosed being employed by Novo Nordisk after the submission of the abstract for presentation at the EASD meeting.
LISBON – A 70% reduction in the risk of hospitalization for heart failure was achieved in people with type 2 diabetes mellitus (T2DM) given an intensified, multifactorial intervention versus conventional treatment in a long-term follow up of the STENO-2 study.
Over 21 years, 34 (21%) of 160 study subjects developed heart failure; 24 (30%) had initially been treated conventionally, and 10 (13%) had initially received intensive treatment. The annualized rates of heart failure were calculated as a respective 2.4% and 0.8% (hazard ratio, 0.30; P less than .002), Jens Øllgaard, PhD, reported at the annual meeting of the European Association for the Study of Diabetes.
Furthermore, after adjustment was made for subject age, gender, prohormone brain natriuretic peptide levels, and ejection fraction at recruitment, there was a 76% relative risk reduction in heart failure with the intensified strategy versus conventional treatment.
“Heart failure in diabetes is frequent, fatal, and at least until very recently, quite forgotten,” said Dr. Øllgaard, who presented the research performed while he was at the STENO Diabetes Center in Copenhagen.
Dr. Øllgaard, who now works for Novo Nordisk, noted that heart failure was four times more likely to occur in patients with T2DM who had microalbuminuria than in those with normal albumin levels in the urine, and the median survival was around 3.5 years. While there is no regulatory requirement at present to stipulate that heart failure should be assessed in trials looking at the cardiovascular safety of T2DM treatments, recording such information is something that the STENO-2 investigators would recommend.
STENO-2 was an open, parallel group study initiated in 1993 to compare conventional multifactorial treatment of T2DM with an intensified approach over an 8-year period. After the primary composite cardiovascular endpoint was assessed, the trial continued as an observational study, with all patients given the intensified, multifactorial treatment that consisted of lifestyle measures and medications targeting hyperglycemia, hypertension, hypercholesterolemia, and hypercoagulation.
The primary endpoint of the long-term follow-up study was the difference in median survival time between the original treatment groups with and without incident cardiovascular disease. The results showed a 48% relative reduction in the risk of death; those initially given the intensified treatment had an increased lifespan of 7.9 years and an 8.1-year increased survival without cardiovascular disease versus those who had initially received conventional treatment (Diabetologica 2016;59:2298-307).
Dr. Øllgaard presented data on heart failure outcomes obtained from a post-hoc analysis of prospectively collected and externally adjudicated patient records.
In addition to the reductions in the primary outcome of time to heart failure, the secondary outcomes of time to heart failure or cardiovascular mortality (HR, 0.38; P = .006) and heart failure or all-cause mortality (relative risk reduction, 49%; P = .001) also favored initial intensive treatment versus conventional treatment.
The number of patients who would need to be treated for 1 year to prevent one heart failure event was 63. The number needed to treat (NNT) to prevent heart failure or cardiovascular death was 48, and the NNT or heart failure or all-cause death was 37.
“Intensified, multifactorial intervention reduces the risk of heart failure and underlines the need for early, intensive treatment in these patients,” Dr. Øllgaard said. “Diabetologists should be aware of this increased risk and the early clinical signs and biomarkers of heart failure.” He added the study “also emphasizes the need for close collaboration, locally and globally, between endocrinologists and cardiologists.”
The STENO-2 long-term follow-up analysis was sponsored by an unrestricted grant from Novo Nordisk. Dr. Øllgaard disclosed being employed by Novo Nordisk after the submission of the abstract for presentation at the EASD meeting.
LISBON – A 70% reduction in the risk of hospitalization for heart failure was achieved in people with type 2 diabetes mellitus (T2DM) given an intensified, multifactorial intervention versus conventional treatment in a long-term follow up of the STENO-2 study.
Over 21 years, 34 (21%) of 160 study subjects developed heart failure; 24 (30%) had initially been treated conventionally, and 10 (13%) had initially received intensive treatment. The annualized rates of heart failure were calculated as a respective 2.4% and 0.8% (hazard ratio, 0.30; P less than .002), Jens Øllgaard, PhD, reported at the annual meeting of the European Association for the Study of Diabetes.
Furthermore, after adjustment was made for subject age, gender, prohormone brain natriuretic peptide levels, and ejection fraction at recruitment, there was a 76% relative risk reduction in heart failure with the intensified strategy versus conventional treatment.
“Heart failure in diabetes is frequent, fatal, and at least until very recently, quite forgotten,” said Dr. Øllgaard, who presented the research performed while he was at the STENO Diabetes Center in Copenhagen.
Dr. Øllgaard, who now works for Novo Nordisk, noted that heart failure was four times more likely to occur in patients with T2DM who had microalbuminuria than in those with normal albumin levels in the urine, and the median survival was around 3.5 years. While there is no regulatory requirement at present to stipulate that heart failure should be assessed in trials looking at the cardiovascular safety of T2DM treatments, recording such information is something that the STENO-2 investigators would recommend.
STENO-2 was an open, parallel group study initiated in 1993 to compare conventional multifactorial treatment of T2DM with an intensified approach over an 8-year period. After the primary composite cardiovascular endpoint was assessed, the trial continued as an observational study, with all patients given the intensified, multifactorial treatment that consisted of lifestyle measures and medications targeting hyperglycemia, hypertension, hypercholesterolemia, and hypercoagulation.
The primary endpoint of the long-term follow-up study was the difference in median survival time between the original treatment groups with and without incident cardiovascular disease. The results showed a 48% relative reduction in the risk of death; those initially given the intensified treatment had an increased lifespan of 7.9 years and an 8.1-year increased survival without cardiovascular disease versus those who had initially received conventional treatment (Diabetologica 2016;59:2298-307).
Dr. Øllgaard presented data on heart failure outcomes obtained from a post-hoc analysis of prospectively collected and externally adjudicated patient records.
In addition to the reductions in the primary outcome of time to heart failure, the secondary outcomes of time to heart failure or cardiovascular mortality (HR, 0.38; P = .006) and heart failure or all-cause mortality (relative risk reduction, 49%; P = .001) also favored initial intensive treatment versus conventional treatment.
The number of patients who would need to be treated for 1 year to prevent one heart failure event was 63. The number needed to treat (NNT) to prevent heart failure or cardiovascular death was 48, and the NNT or heart failure or all-cause death was 37.
“Intensified, multifactorial intervention reduces the risk of heart failure and underlines the need for early, intensive treatment in these patients,” Dr. Øllgaard said. “Diabetologists should be aware of this increased risk and the early clinical signs and biomarkers of heart failure.” He added the study “also emphasizes the need for close collaboration, locally and globally, between endocrinologists and cardiologists.”
The STENO-2 long-term follow-up analysis was sponsored by an unrestricted grant from Novo Nordisk. Dr. Øllgaard disclosed being employed by Novo Nordisk after the submission of the abstract for presentation at the EASD meeting.
AT EASD 2017
Key clinical point: Intensified, multifactorial treatment reduces the risk of heart failure in people with type 2 diabetes mellitus versus a conventional treatment approach.
Major finding: The risk of heart failure was reduced by 70% (P = .002).
Data source: Post hoc analysis from 21 years follow-up on the Steno-2 randomized trial conducted in 160 patients with type 2 diabetes and microalbuminuria who were randomized to an intensive or conventional treatment arm.
Disclosures: The STENO-2 long-term follow-up analysis was sponsored by an unrestricted grant from Novo Nordisk. Dr. Øllgaard disclosed being employed by Novo Nordisk after the submission of the abstract for presentation at the EASD meeting.
Semaglutide aids T2DM weight loss over 2 years
LISBON – The investigational glucagon-like peptide (GLP)-1 receptor agonist semaglutide added to standard care for type 2 diabetes mellitus (T2DM) resulted in clinically significant weight loss over 2 years in the SUSTAIN-6 phase 3 trial.
Participants treated with semaglutide in the study lost an average of 3.6 to 4.9 kg, depending on the dose they were given (0.5 mg or 1.0 mg), which was significantly (P less than .0001) more than those who were randomized to matching placebos (-0.7 mg and -0.5 mg).
Semaglutide is under development by Novo Nordisk and is currently under review by regulatory agencies in the United States, Europe, and Japan. It has 94% homology to human GLP-1 and modifications have been made to help it avoid degradation and which give it a half-life that allows it to be given once a week.
SUSTAIN 6 is part of an ongoing phase 3 program and is a long-term outcome study with the primary objective of evaluating the cardiovascular safety of semaglutide. Effects on macro- and microvascular complications, glycemic control, body weight, body mass index and weight circumference are key secondary endpoints, together with assessment of its overall safety and tolerability.
Other trials in the program, have evaluated treatment with semaglutide as monotherapy (SUSTAIN 1; Lancet Diabetes Endocrinol. 2017;5:251-60) or versus other treatments including sitagliptin (Januvia, Merck; SUSTAIN 2; Lancet Diabetes Endocrinol. 2017;5:341-54), exenatide extended release (Bydureon, AstraZeneca; SUSTAIN 3), or insulin glargine (SUSTAIN 4), as add-on to basal insulin with or without metformin (SUSTAIN 5), and most recently, versus dulaglutide (Trulicity, Eli Lilly; SUSTAIN 7).
SUSTAIN 6 involved 3,297 people with T2DM with established cardiovascular disease or chronic kidney disease or otherwise identified as being at increased cardiovascular risk, according to Dr. Consoli, who is an endocrinologist and professor at the University of Chieti-Pescara, Italy. The results of the primary endpoint have been reported (N Engl J Med. 2016; 375:1834-44) and showed that the composite rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo. The hazard ratio for the reduction in the composite endpoint was 0.74 (95% CI, 0.58-.95; P less than .001 for noninferiority).
Results of the secondary analyses reported by Dr. Consoli at EASD 2017 showed that semaglutide could help more patients than placebo achieve significant weight loss, which could help further reduce their cardiovascular risk. He reported that a 5% or greater weight loss at 2 years was achieved by 36% and 47% of patients treated with semaglutide 0.5 mg and 1 mg groups, respectively, and by 18% and 19% of patients in the matching placebo groups (P less than .0001 for both comparisons). A 10% or greater weight loss was achieved by 13% and 21% of the semaglutide-treated patients and by 6% and 7% of those given placebo.
“The effect of weight was not dependent on BMI [body mass index] at baseline,” Dr. Consoli said, emphasizing that there was a consistent reduction in the weight in all BMI categories. Importantly, Dr. Consoli observed, the effects of semaglutide on weight seen were not driven by just a few patients losing weight, and around 80% of patients in the study experienced some degree of weight loss.
“As expected, the subjects treated with the GLP-1a had more GI [gastrointestinal] effects,” Dr. Consoli reported. Nausea or vomiting were reported in twice as many patients treated with semaglutide 0.5 mg (21.9%) and 1 mg (27.3%) as their placebo-matched counterparts (10.8% and 10.6%).
A post-hoc analysis found that the effect of semaglutide on weight loss was not likely to be down to these side effects, however, with a similar weight reductions seen in those who did and did not experience nausea or vomiting. The “estimated natural direct effect of treatment” was -2.75 kg for the 0.5 mg dose and -4.32 for the 1 mg dose of semaglutide versus their placebos Dr. Consoli said. GI drove the weigjht loss to a small degree; -0.12 kg and -0.04 kg of weight loss seen in the 0.5 mg and 1 mg semaglutide groups versus their placebos could be ascribed to nausea or vomiting.
In a poster presentation at the meeting, data on another post-hoc analysis from the SUSTAIN phase 3 program were reported. In a responder analysis of T2DM patients achieving glycemic and weight loss thresholds, a greater proportion of those treated with semaglutide achieved clinically meaningful reductions in both glycated hemoglobin (HbA1c) and body weight than those given comparator treatments.
The composite endpoint of at least a 1% reduction in HbA1c and a 5% or greater decrease in body weight was achieved by 25%–35% of patients treated with the 0.5 mg dose of semaglutide, by 38%–56% of those given the higher dose, and by 2%–13% or all comparators (P less than .0001). The higher dose of semaglutide also allowed more people to achieve this endpoint than the lower dose.
Novo Nordisk supported the study. Dr. Consoli disclosed receiving research funding from AstraZeneca and Novo Nordisk and speaker’s bureau or consultation fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., Merck, Sharp & Dohme, Novartis, Sanofi-Aventis, and Takeda.
LISBON – The investigational glucagon-like peptide (GLP)-1 receptor agonist semaglutide added to standard care for type 2 diabetes mellitus (T2DM) resulted in clinically significant weight loss over 2 years in the SUSTAIN-6 phase 3 trial.
Participants treated with semaglutide in the study lost an average of 3.6 to 4.9 kg, depending on the dose they were given (0.5 mg or 1.0 mg), which was significantly (P less than .0001) more than those who were randomized to matching placebos (-0.7 mg and -0.5 mg).
Semaglutide is under development by Novo Nordisk and is currently under review by regulatory agencies in the United States, Europe, and Japan. It has 94% homology to human GLP-1 and modifications have been made to help it avoid degradation and which give it a half-life that allows it to be given once a week.
SUSTAIN 6 is part of an ongoing phase 3 program and is a long-term outcome study with the primary objective of evaluating the cardiovascular safety of semaglutide. Effects on macro- and microvascular complications, glycemic control, body weight, body mass index and weight circumference are key secondary endpoints, together with assessment of its overall safety and tolerability.
Other trials in the program, have evaluated treatment with semaglutide as monotherapy (SUSTAIN 1; Lancet Diabetes Endocrinol. 2017;5:251-60) or versus other treatments including sitagliptin (Januvia, Merck; SUSTAIN 2; Lancet Diabetes Endocrinol. 2017;5:341-54), exenatide extended release (Bydureon, AstraZeneca; SUSTAIN 3), or insulin glargine (SUSTAIN 4), as add-on to basal insulin with or without metformin (SUSTAIN 5), and most recently, versus dulaglutide (Trulicity, Eli Lilly; SUSTAIN 7).
SUSTAIN 6 involved 3,297 people with T2DM with established cardiovascular disease or chronic kidney disease or otherwise identified as being at increased cardiovascular risk, according to Dr. Consoli, who is an endocrinologist and professor at the University of Chieti-Pescara, Italy. The results of the primary endpoint have been reported (N Engl J Med. 2016; 375:1834-44) and showed that the composite rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo. The hazard ratio for the reduction in the composite endpoint was 0.74 (95% CI, 0.58-.95; P less than .001 for noninferiority).
Results of the secondary analyses reported by Dr. Consoli at EASD 2017 showed that semaglutide could help more patients than placebo achieve significant weight loss, which could help further reduce their cardiovascular risk. He reported that a 5% or greater weight loss at 2 years was achieved by 36% and 47% of patients treated with semaglutide 0.5 mg and 1 mg groups, respectively, and by 18% and 19% of patients in the matching placebo groups (P less than .0001 for both comparisons). A 10% or greater weight loss was achieved by 13% and 21% of the semaglutide-treated patients and by 6% and 7% of those given placebo.
“The effect of weight was not dependent on BMI [body mass index] at baseline,” Dr. Consoli said, emphasizing that there was a consistent reduction in the weight in all BMI categories. Importantly, Dr. Consoli observed, the effects of semaglutide on weight seen were not driven by just a few patients losing weight, and around 80% of patients in the study experienced some degree of weight loss.
“As expected, the subjects treated with the GLP-1a had more GI [gastrointestinal] effects,” Dr. Consoli reported. Nausea or vomiting were reported in twice as many patients treated with semaglutide 0.5 mg (21.9%) and 1 mg (27.3%) as their placebo-matched counterparts (10.8% and 10.6%).
A post-hoc analysis found that the effect of semaglutide on weight loss was not likely to be down to these side effects, however, with a similar weight reductions seen in those who did and did not experience nausea or vomiting. The “estimated natural direct effect of treatment” was -2.75 kg for the 0.5 mg dose and -4.32 for the 1 mg dose of semaglutide versus their placebos Dr. Consoli said. GI drove the weigjht loss to a small degree; -0.12 kg and -0.04 kg of weight loss seen in the 0.5 mg and 1 mg semaglutide groups versus their placebos could be ascribed to nausea or vomiting.
In a poster presentation at the meeting, data on another post-hoc analysis from the SUSTAIN phase 3 program were reported. In a responder analysis of T2DM patients achieving glycemic and weight loss thresholds, a greater proportion of those treated with semaglutide achieved clinically meaningful reductions in both glycated hemoglobin (HbA1c) and body weight than those given comparator treatments.
The composite endpoint of at least a 1% reduction in HbA1c and a 5% or greater decrease in body weight was achieved by 25%–35% of patients treated with the 0.5 mg dose of semaglutide, by 38%–56% of those given the higher dose, and by 2%–13% or all comparators (P less than .0001). The higher dose of semaglutide also allowed more people to achieve this endpoint than the lower dose.
Novo Nordisk supported the study. Dr. Consoli disclosed receiving research funding from AstraZeneca and Novo Nordisk and speaker’s bureau or consultation fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., Merck, Sharp & Dohme, Novartis, Sanofi-Aventis, and Takeda.
LISBON – The investigational glucagon-like peptide (GLP)-1 receptor agonist semaglutide added to standard care for type 2 diabetes mellitus (T2DM) resulted in clinically significant weight loss over 2 years in the SUSTAIN-6 phase 3 trial.
Participants treated with semaglutide in the study lost an average of 3.6 to 4.9 kg, depending on the dose they were given (0.5 mg or 1.0 mg), which was significantly (P less than .0001) more than those who were randomized to matching placebos (-0.7 mg and -0.5 mg).
Semaglutide is under development by Novo Nordisk and is currently under review by regulatory agencies in the United States, Europe, and Japan. It has 94% homology to human GLP-1 and modifications have been made to help it avoid degradation and which give it a half-life that allows it to be given once a week.
SUSTAIN 6 is part of an ongoing phase 3 program and is a long-term outcome study with the primary objective of evaluating the cardiovascular safety of semaglutide. Effects on macro- and microvascular complications, glycemic control, body weight, body mass index and weight circumference are key secondary endpoints, together with assessment of its overall safety and tolerability.
Other trials in the program, have evaluated treatment with semaglutide as monotherapy (SUSTAIN 1; Lancet Diabetes Endocrinol. 2017;5:251-60) or versus other treatments including sitagliptin (Januvia, Merck; SUSTAIN 2; Lancet Diabetes Endocrinol. 2017;5:341-54), exenatide extended release (Bydureon, AstraZeneca; SUSTAIN 3), or insulin glargine (SUSTAIN 4), as add-on to basal insulin with or without metformin (SUSTAIN 5), and most recently, versus dulaglutide (Trulicity, Eli Lilly; SUSTAIN 7).
SUSTAIN 6 involved 3,297 people with T2DM with established cardiovascular disease or chronic kidney disease or otherwise identified as being at increased cardiovascular risk, according to Dr. Consoli, who is an endocrinologist and professor at the University of Chieti-Pescara, Italy. The results of the primary endpoint have been reported (N Engl J Med. 2016; 375:1834-44) and showed that the composite rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo. The hazard ratio for the reduction in the composite endpoint was 0.74 (95% CI, 0.58-.95; P less than .001 for noninferiority).
Results of the secondary analyses reported by Dr. Consoli at EASD 2017 showed that semaglutide could help more patients than placebo achieve significant weight loss, which could help further reduce their cardiovascular risk. He reported that a 5% or greater weight loss at 2 years was achieved by 36% and 47% of patients treated with semaglutide 0.5 mg and 1 mg groups, respectively, and by 18% and 19% of patients in the matching placebo groups (P less than .0001 for both comparisons). A 10% or greater weight loss was achieved by 13% and 21% of the semaglutide-treated patients and by 6% and 7% of those given placebo.
“The effect of weight was not dependent on BMI [body mass index] at baseline,” Dr. Consoli said, emphasizing that there was a consistent reduction in the weight in all BMI categories. Importantly, Dr. Consoli observed, the effects of semaglutide on weight seen were not driven by just a few patients losing weight, and around 80% of patients in the study experienced some degree of weight loss.
“As expected, the subjects treated with the GLP-1a had more GI [gastrointestinal] effects,” Dr. Consoli reported. Nausea or vomiting were reported in twice as many patients treated with semaglutide 0.5 mg (21.9%) and 1 mg (27.3%) as their placebo-matched counterparts (10.8% and 10.6%).
A post-hoc analysis found that the effect of semaglutide on weight loss was not likely to be down to these side effects, however, with a similar weight reductions seen in those who did and did not experience nausea or vomiting. The “estimated natural direct effect of treatment” was -2.75 kg for the 0.5 mg dose and -4.32 for the 1 mg dose of semaglutide versus their placebos Dr. Consoli said. GI drove the weigjht loss to a small degree; -0.12 kg and -0.04 kg of weight loss seen in the 0.5 mg and 1 mg semaglutide groups versus their placebos could be ascribed to nausea or vomiting.
In a poster presentation at the meeting, data on another post-hoc analysis from the SUSTAIN phase 3 program were reported. In a responder analysis of T2DM patients achieving glycemic and weight loss thresholds, a greater proportion of those treated with semaglutide achieved clinically meaningful reductions in both glycated hemoglobin (HbA1c) and body weight than those given comparator treatments.
The composite endpoint of at least a 1% reduction in HbA1c and a 5% or greater decrease in body weight was achieved by 25%–35% of patients treated with the 0.5 mg dose of semaglutide, by 38%–56% of those given the higher dose, and by 2%–13% or all comparators (P less than .0001). The higher dose of semaglutide also allowed more people to achieve this endpoint than the lower dose.
Novo Nordisk supported the study. Dr. Consoli disclosed receiving research funding from AstraZeneca and Novo Nordisk and speaker’s bureau or consultation fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., Merck, Sharp & Dohme, Novartis, Sanofi-Aventis, and Takeda.
AT EASD 2017
Key clinical point: Semaglutide added to standard of care was associated with significant weight loss independent of any gastrointestinal side effects.
Major finding: There was a -2.87 kg to -4.35 kg change in body weight comparing two doses of semaglutide with matching placebos (both P less than .0001).
Data source: SUSTAIN-6: A long-term outcomes study in 3,297 patients with type 2 diabetes treated with once-weekly semaglutide or placebo for 104 weeks.
Disclosures: Novo Nordisk supported the study. Dr. Consoli disclosed receiving research funding from AstraZeneca and Novo Nordisk and speaker’s bureau or consultation fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Sharp & Dohme, Novartis, Sanofi-Aventis, and Takeda.
Fasting glucose fluctuations, severe hypoglycemia up T2DM death risk
AT EASD 2017
LISBON –
A second wave of results from the DEVOTE study, which compared the cardiovascular safety of insulin degludec (Tresiba, Novo Nordisk) versus insulin glargine, found that day-to-day variability in fasting plasma glucose (FPG) versus no FPG variability was significantly associated with both severe hypoglycemia (adjusted hazard ratio, 3.37; 95% confidence interval, 2.52-4.50; P less than .001), and all-cause mortality (aHR, 1.33; 95% CI, 1.01-1.75; P = .00432).
In addition, severe hypoglycemia was linked to all-cause mortality, with a temporal relationship seen such that the risk for death was higher the more recent the episode of severe hypoglycemia had been. Indeed, while the risk of death was 2.5 times higher at any time after an episode of severe hypoglycemia than if no prior severe hypoglycemia occurred (HR, 2.51; 95% CI, 1.35-13.09), it was four times higher 15 days after severe hypoglycemia than after no such event (HR, 4.20; 95% CI, 1.9-3.50).
These results of DEVOTE 2 and DEVOTE 3 were presented at the annual meeting of the European Association for the Study of Diabetes and published in Diabetologia on Sept. 15.
What do the results mean for current practice?
“There’s great interest in knowing whether glucose variability and severe hypoglycemia are associated with cardiovascular risk and mortality; these data are therefore important and timely,” said the invited commentator and editorialist for the study Martin Rutter, MD, a senior lecturer in cardiometabolic medicine at the University of Manchester and an honorary consultant physician at Manchester Royal Infirmary, England.
“Only further clinical trials can genuinely guide clinicians on whether to target glucose variability and risk for severe hypos to reduce the risk of cardiovascular events in people with type 2 diabetes. My hope is that these data will help to build a case for such trials,” Dr. Rutter said.
DEVOTE: main findings and secondary analyses
The main findings from the DEVOTE study were reported in June during the American Diabetes Association’s Annual Scientific Sessions and simultaneously published in the New England Journal of Medicine (2017 Aug 24;377[8]:723-32). These showed that insulin degludec was noninferior to insulin glargine, with a similar rate of major cardiovascular events (MACE), which comprised nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death (8.5% vs. 9.3%; HR, 0.91; 95% CI, 0.78-1.06; P less than .001). The rate of severe hypoglycemia was significantly (P less than .001) lower in the degludec than glargine arm, however, occurring in a respective 4.9% and 6.6% of patients in each group (odds ratio, 0.73).
“DEVOTE confirms the cardiovascular safety of insulin degludec, compared with glargine,” said DEVOTE study investigator, Neil Poulter, MD, FMedSci, of the Imperial Clinical Trials Unit at Imperial College London. “The rate of severe hypoglycemia was significantly reduced [with insulin degludec vs. glargine] in the DEVOTE trial.”
Role of glycemic variability
“It is well established that there is a relationship between glycemic variability and hypoglycemia,” said Bernard Zinman, MD, director of the Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital in Toronto, who presented the DEVOTE 2 findings. He commented that the “very dense data” collected during the main study had enabled a fuller analysis of glycemic variability. Dr. Zinman was keen to emphasize that it was the fasting variability that was studied.
Looking at outcomes, there was a dose relationship seen from low to high glycemic variability with increasing rates of severe hypoglycemia, MACE, and all-cause mortality the higher the variability, Dr. Zinman reported.
Although initially there was an increased risk for MACE with increasing glycemic variability, “the association was not maintained after adjusting for baseline characteristics and the most recent A1c,” Dr. Zinman said.
Timing of severe hypoglycemia could be vital
Severe hypoglycemia is under-reported and there is still concern over inducing hypoglycemia, which “conflicts with treatment success,” observed Thomas Pieber, MD, who presented the DEVOTE 3 findings on the relationship between severe hypoglycemia and outcomes.
“Up to 80% of us are concerned about the risk of hypoglycemia and we are not treating glycemic control as aggressively as we would do if there was not any worry about hypoglycemia,” Dr. Pieber said, referring to primary care physicians and diabetes specialists.
Talking about the DEVOTE 3 results, Dr. Pieber noted: “There was no significant association between severe hypoglycemia and MACE, but there was a significantly higher risk of cardiovascular death following a severe hypoglycemia event.” He reminded the audience that an episode of severe hypoglycemia was one which required the assistance of another person, as defined by International Hypoglycemia Study Group which has been acknowledged by both the ADA and EASD.
“These data we have analyzed support a temporal relationship between severe hypoglycemia and all-cause mortality,” Dr. Pieber, adding “the findings indicate that severe hypoglycemia is associated with higher subsequent mortality.”
Predicting severe hypos
“There are well-known factors that influence the risk of having a severe hypoglycemic event,” commented another of the DEVOTE study investigators, John Buse, MD, PhD, of the University of North Carolina School of Medicine at Chapel Hill. These include the insulin treatment regimen, the duration of diabetes, sex, and baseline HbA1c, to pick the more traditional ones. Additional ones that a post-hoc analysis of the DEVOTE data identified are baseline renal function, prior stroke, low-to-high-density lipoprotein ratio, diastolic blood pressure, hepatic impairment, and smoking status. Age, another traditional risk factor, was identified as well and all these went in to create the DEVOTE severe hypoglycemia risk prediction model.
The DEVOTE hypoglycemia risk score is currently a work in progress; the app can be seen at http://www.hyporiskscore.com/. DEVOTE was funded by Novo Nordisk. Slides presented at the EASD meeting are available for download at https://tracs.unc.edu/DEVOTE.
Dr. Rutter disclosed receiving honoraria and funding to attend educational meetings from Novo Nordisk and honoraria and consulting fees from Ascensia, Cell Catapult, and Roche Diabetes Care.
Dr. Poulter has received speaker fees and consultancy fees from Novo Nordisk, Servier, Takeda, and AstraZeneca; and grants for his research group relating to type 2 diabetes mellitus from Diabetes UK, the National Institute for Health Research Efficacy and Mechanism Evaluation, and the Julius Clinical and the British Heart Foundation.
Dr. Zinman has received grant support from Novo Nordisk, Boehringer Ingelheim, and AstraZeneca. He disclosed receiving consulting fees from Novo Nordisk, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck, Sharp & Dohme, and Sanofi.
Dr. Pieber disclosed receiving received research support from Novo Nordisk and AstraZeneca paid directly to his institution and personal honoraria from Novo Nordisk, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Roche Diabetes Care. Dr. Pieber is the Chief Scientific Officer of the Center for Biomarker Research in Medicine, a publicly funded biomarker research company.
Dr. Buse reported receiving contracted consulting fees, paid to his institution, and travel support from Novo Nordisk, Eli Lilly and Company, GI Dynamics, Elcelyx, Merck, Metavention, vTv Pharma, PhaseBio, AstraZeneca, Dance Biopharm, Sanofi, Lexicon Pharmaceuticals, Orexigen, Takeda, Adocia, Roche, NovaTarg, Shenzhen High Tide, Fractyl, and Dexcom. He has also received consultancy fees and grant support from Eli Lilly and Company, Bristol-Myers Squibb, GI Dynamics, Merck, PhaseBio, AstraZeneca, Medtronic Minimed, Sanofi, Johnson & Johnson, Andromeda, Boehringer Ingelheim, GlaxoSmithKline, MacroGenics, Intarcia Therapeutics, Lexicon Pharmaceuticals, Scion NeuroStim, Orexigen, Takeda, Theracos, and Bayer. Dr. Buse has also received fees and holds stock options in PhaseBio and Insulin Algorithm, as well as serving on the board of the AstraZeneca Healthcare Foundation.
AT EASD 2017
LISBON –
A second wave of results from the DEVOTE study, which compared the cardiovascular safety of insulin degludec (Tresiba, Novo Nordisk) versus insulin glargine, found that day-to-day variability in fasting plasma glucose (FPG) versus no FPG variability was significantly associated with both severe hypoglycemia (adjusted hazard ratio, 3.37; 95% confidence interval, 2.52-4.50; P less than .001), and all-cause mortality (aHR, 1.33; 95% CI, 1.01-1.75; P = .00432).
In addition, severe hypoglycemia was linked to all-cause mortality, with a temporal relationship seen such that the risk for death was higher the more recent the episode of severe hypoglycemia had been. Indeed, while the risk of death was 2.5 times higher at any time after an episode of severe hypoglycemia than if no prior severe hypoglycemia occurred (HR, 2.51; 95% CI, 1.35-13.09), it was four times higher 15 days after severe hypoglycemia than after no such event (HR, 4.20; 95% CI, 1.9-3.50).
These results of DEVOTE 2 and DEVOTE 3 were presented at the annual meeting of the European Association for the Study of Diabetes and published in Diabetologia on Sept. 15.
What do the results mean for current practice?
“There’s great interest in knowing whether glucose variability and severe hypoglycemia are associated with cardiovascular risk and mortality; these data are therefore important and timely,” said the invited commentator and editorialist for the study Martin Rutter, MD, a senior lecturer in cardiometabolic medicine at the University of Manchester and an honorary consultant physician at Manchester Royal Infirmary, England.
“Only further clinical trials can genuinely guide clinicians on whether to target glucose variability and risk for severe hypos to reduce the risk of cardiovascular events in people with type 2 diabetes. My hope is that these data will help to build a case for such trials,” Dr. Rutter said.
DEVOTE: main findings and secondary analyses
The main findings from the DEVOTE study were reported in June during the American Diabetes Association’s Annual Scientific Sessions and simultaneously published in the New England Journal of Medicine (2017 Aug 24;377[8]:723-32). These showed that insulin degludec was noninferior to insulin glargine, with a similar rate of major cardiovascular events (MACE), which comprised nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death (8.5% vs. 9.3%; HR, 0.91; 95% CI, 0.78-1.06; P less than .001). The rate of severe hypoglycemia was significantly (P less than .001) lower in the degludec than glargine arm, however, occurring in a respective 4.9% and 6.6% of patients in each group (odds ratio, 0.73).
“DEVOTE confirms the cardiovascular safety of insulin degludec, compared with glargine,” said DEVOTE study investigator, Neil Poulter, MD, FMedSci, of the Imperial Clinical Trials Unit at Imperial College London. “The rate of severe hypoglycemia was significantly reduced [with insulin degludec vs. glargine] in the DEVOTE trial.”
Role of glycemic variability
“It is well established that there is a relationship between glycemic variability and hypoglycemia,” said Bernard Zinman, MD, director of the Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital in Toronto, who presented the DEVOTE 2 findings. He commented that the “very dense data” collected during the main study had enabled a fuller analysis of glycemic variability. Dr. Zinman was keen to emphasize that it was the fasting variability that was studied.
Looking at outcomes, there was a dose relationship seen from low to high glycemic variability with increasing rates of severe hypoglycemia, MACE, and all-cause mortality the higher the variability, Dr. Zinman reported.
Although initially there was an increased risk for MACE with increasing glycemic variability, “the association was not maintained after adjusting for baseline characteristics and the most recent A1c,” Dr. Zinman said.
Timing of severe hypoglycemia could be vital
Severe hypoglycemia is under-reported and there is still concern over inducing hypoglycemia, which “conflicts with treatment success,” observed Thomas Pieber, MD, who presented the DEVOTE 3 findings on the relationship between severe hypoglycemia and outcomes.
“Up to 80% of us are concerned about the risk of hypoglycemia and we are not treating glycemic control as aggressively as we would do if there was not any worry about hypoglycemia,” Dr. Pieber said, referring to primary care physicians and diabetes specialists.
Talking about the DEVOTE 3 results, Dr. Pieber noted: “There was no significant association between severe hypoglycemia and MACE, but there was a significantly higher risk of cardiovascular death following a severe hypoglycemia event.” He reminded the audience that an episode of severe hypoglycemia was one which required the assistance of another person, as defined by International Hypoglycemia Study Group which has been acknowledged by both the ADA and EASD.
“These data we have analyzed support a temporal relationship between severe hypoglycemia and all-cause mortality,” Dr. Pieber, adding “the findings indicate that severe hypoglycemia is associated with higher subsequent mortality.”
Predicting severe hypos
“There are well-known factors that influence the risk of having a severe hypoglycemic event,” commented another of the DEVOTE study investigators, John Buse, MD, PhD, of the University of North Carolina School of Medicine at Chapel Hill. These include the insulin treatment regimen, the duration of diabetes, sex, and baseline HbA1c, to pick the more traditional ones. Additional ones that a post-hoc analysis of the DEVOTE data identified are baseline renal function, prior stroke, low-to-high-density lipoprotein ratio, diastolic blood pressure, hepatic impairment, and smoking status. Age, another traditional risk factor, was identified as well and all these went in to create the DEVOTE severe hypoglycemia risk prediction model.
The DEVOTE hypoglycemia risk score is currently a work in progress; the app can be seen at http://www.hyporiskscore.com/. DEVOTE was funded by Novo Nordisk. Slides presented at the EASD meeting are available for download at https://tracs.unc.edu/DEVOTE.
Dr. Rutter disclosed receiving honoraria and funding to attend educational meetings from Novo Nordisk and honoraria and consulting fees from Ascensia, Cell Catapult, and Roche Diabetes Care.
Dr. Poulter has received speaker fees and consultancy fees from Novo Nordisk, Servier, Takeda, and AstraZeneca; and grants for his research group relating to type 2 diabetes mellitus from Diabetes UK, the National Institute for Health Research Efficacy and Mechanism Evaluation, and the Julius Clinical and the British Heart Foundation.
Dr. Zinman has received grant support from Novo Nordisk, Boehringer Ingelheim, and AstraZeneca. He disclosed receiving consulting fees from Novo Nordisk, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck, Sharp & Dohme, and Sanofi.
Dr. Pieber disclosed receiving received research support from Novo Nordisk and AstraZeneca paid directly to his institution and personal honoraria from Novo Nordisk, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Roche Diabetes Care. Dr. Pieber is the Chief Scientific Officer of the Center for Biomarker Research in Medicine, a publicly funded biomarker research company.
Dr. Buse reported receiving contracted consulting fees, paid to his institution, and travel support from Novo Nordisk, Eli Lilly and Company, GI Dynamics, Elcelyx, Merck, Metavention, vTv Pharma, PhaseBio, AstraZeneca, Dance Biopharm, Sanofi, Lexicon Pharmaceuticals, Orexigen, Takeda, Adocia, Roche, NovaTarg, Shenzhen High Tide, Fractyl, and Dexcom. He has also received consultancy fees and grant support from Eli Lilly and Company, Bristol-Myers Squibb, GI Dynamics, Merck, PhaseBio, AstraZeneca, Medtronic Minimed, Sanofi, Johnson & Johnson, Andromeda, Boehringer Ingelheim, GlaxoSmithKline, MacroGenics, Intarcia Therapeutics, Lexicon Pharmaceuticals, Scion NeuroStim, Orexigen, Takeda, Theracos, and Bayer. Dr. Buse has also received fees and holds stock options in PhaseBio and Insulin Algorithm, as well as serving on the board of the AstraZeneca Healthcare Foundation.
AT EASD 2017
LISBON –
A second wave of results from the DEVOTE study, which compared the cardiovascular safety of insulin degludec (Tresiba, Novo Nordisk) versus insulin glargine, found that day-to-day variability in fasting plasma glucose (FPG) versus no FPG variability was significantly associated with both severe hypoglycemia (adjusted hazard ratio, 3.37; 95% confidence interval, 2.52-4.50; P less than .001), and all-cause mortality (aHR, 1.33; 95% CI, 1.01-1.75; P = .00432).
In addition, severe hypoglycemia was linked to all-cause mortality, with a temporal relationship seen such that the risk for death was higher the more recent the episode of severe hypoglycemia had been. Indeed, while the risk of death was 2.5 times higher at any time after an episode of severe hypoglycemia than if no prior severe hypoglycemia occurred (HR, 2.51; 95% CI, 1.35-13.09), it was four times higher 15 days after severe hypoglycemia than after no such event (HR, 4.20; 95% CI, 1.9-3.50).
These results of DEVOTE 2 and DEVOTE 3 were presented at the annual meeting of the European Association for the Study of Diabetes and published in Diabetologia on Sept. 15.
What do the results mean for current practice?
“There’s great interest in knowing whether glucose variability and severe hypoglycemia are associated with cardiovascular risk and mortality; these data are therefore important and timely,” said the invited commentator and editorialist for the study Martin Rutter, MD, a senior lecturer in cardiometabolic medicine at the University of Manchester and an honorary consultant physician at Manchester Royal Infirmary, England.
“Only further clinical trials can genuinely guide clinicians on whether to target glucose variability and risk for severe hypos to reduce the risk of cardiovascular events in people with type 2 diabetes. My hope is that these data will help to build a case for such trials,” Dr. Rutter said.
DEVOTE: main findings and secondary analyses
The main findings from the DEVOTE study were reported in June during the American Diabetes Association’s Annual Scientific Sessions and simultaneously published in the New England Journal of Medicine (2017 Aug 24;377[8]:723-32). These showed that insulin degludec was noninferior to insulin glargine, with a similar rate of major cardiovascular events (MACE), which comprised nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death (8.5% vs. 9.3%; HR, 0.91; 95% CI, 0.78-1.06; P less than .001). The rate of severe hypoglycemia was significantly (P less than .001) lower in the degludec than glargine arm, however, occurring in a respective 4.9% and 6.6% of patients in each group (odds ratio, 0.73).
“DEVOTE confirms the cardiovascular safety of insulin degludec, compared with glargine,” said DEVOTE study investigator, Neil Poulter, MD, FMedSci, of the Imperial Clinical Trials Unit at Imperial College London. “The rate of severe hypoglycemia was significantly reduced [with insulin degludec vs. glargine] in the DEVOTE trial.”
Role of glycemic variability
“It is well established that there is a relationship between glycemic variability and hypoglycemia,” said Bernard Zinman, MD, director of the Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital in Toronto, who presented the DEVOTE 2 findings. He commented that the “very dense data” collected during the main study had enabled a fuller analysis of glycemic variability. Dr. Zinman was keen to emphasize that it was the fasting variability that was studied.
Looking at outcomes, there was a dose relationship seen from low to high glycemic variability with increasing rates of severe hypoglycemia, MACE, and all-cause mortality the higher the variability, Dr. Zinman reported.
Although initially there was an increased risk for MACE with increasing glycemic variability, “the association was not maintained after adjusting for baseline characteristics and the most recent A1c,” Dr. Zinman said.
Timing of severe hypoglycemia could be vital
Severe hypoglycemia is under-reported and there is still concern over inducing hypoglycemia, which “conflicts with treatment success,” observed Thomas Pieber, MD, who presented the DEVOTE 3 findings on the relationship between severe hypoglycemia and outcomes.
“Up to 80% of us are concerned about the risk of hypoglycemia and we are not treating glycemic control as aggressively as we would do if there was not any worry about hypoglycemia,” Dr. Pieber said, referring to primary care physicians and diabetes specialists.
Talking about the DEVOTE 3 results, Dr. Pieber noted: “There was no significant association between severe hypoglycemia and MACE, but there was a significantly higher risk of cardiovascular death following a severe hypoglycemia event.” He reminded the audience that an episode of severe hypoglycemia was one which required the assistance of another person, as defined by International Hypoglycemia Study Group which has been acknowledged by both the ADA and EASD.
“These data we have analyzed support a temporal relationship between severe hypoglycemia and all-cause mortality,” Dr. Pieber, adding “the findings indicate that severe hypoglycemia is associated with higher subsequent mortality.”
Predicting severe hypos
“There are well-known factors that influence the risk of having a severe hypoglycemic event,” commented another of the DEVOTE study investigators, John Buse, MD, PhD, of the University of North Carolina School of Medicine at Chapel Hill. These include the insulin treatment regimen, the duration of diabetes, sex, and baseline HbA1c, to pick the more traditional ones. Additional ones that a post-hoc analysis of the DEVOTE data identified are baseline renal function, prior stroke, low-to-high-density lipoprotein ratio, diastolic blood pressure, hepatic impairment, and smoking status. Age, another traditional risk factor, was identified as well and all these went in to create the DEVOTE severe hypoglycemia risk prediction model.
The DEVOTE hypoglycemia risk score is currently a work in progress; the app can be seen at http://www.hyporiskscore.com/. DEVOTE was funded by Novo Nordisk. Slides presented at the EASD meeting are available for download at https://tracs.unc.edu/DEVOTE.
Dr. Rutter disclosed receiving honoraria and funding to attend educational meetings from Novo Nordisk and honoraria and consulting fees from Ascensia, Cell Catapult, and Roche Diabetes Care.
Dr. Poulter has received speaker fees and consultancy fees from Novo Nordisk, Servier, Takeda, and AstraZeneca; and grants for his research group relating to type 2 diabetes mellitus from Diabetes UK, the National Institute for Health Research Efficacy and Mechanism Evaluation, and the Julius Clinical and the British Heart Foundation.
Dr. Zinman has received grant support from Novo Nordisk, Boehringer Ingelheim, and AstraZeneca. He disclosed receiving consulting fees from Novo Nordisk, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck, Sharp & Dohme, and Sanofi.
Dr. Pieber disclosed receiving received research support from Novo Nordisk and AstraZeneca paid directly to his institution and personal honoraria from Novo Nordisk, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Roche Diabetes Care. Dr. Pieber is the Chief Scientific Officer of the Center for Biomarker Research in Medicine, a publicly funded biomarker research company.
Dr. Buse reported receiving contracted consulting fees, paid to his institution, and travel support from Novo Nordisk, Eli Lilly and Company, GI Dynamics, Elcelyx, Merck, Metavention, vTv Pharma, PhaseBio, AstraZeneca, Dance Biopharm, Sanofi, Lexicon Pharmaceuticals, Orexigen, Takeda, Adocia, Roche, NovaTarg, Shenzhen High Tide, Fractyl, and Dexcom. He has also received consultancy fees and grant support from Eli Lilly and Company, Bristol-Myers Squibb, GI Dynamics, Merck, PhaseBio, AstraZeneca, Medtronic Minimed, Sanofi, Johnson & Johnson, Andromeda, Boehringer Ingelheim, GlaxoSmithKline, MacroGenics, Intarcia Therapeutics, Lexicon Pharmaceuticals, Scion NeuroStim, Orexigen, Takeda, Theracos, and Bayer. Dr. Buse has also received fees and holds stock options in PhaseBio and Insulin Algorithm, as well as serving on the board of the AstraZeneca Healthcare Foundation.
Key clinical point: Evenly maintained blood glucose levels may save lives in T2DM.
Major finding: Patients with greater fluctuations of fasting plasma glucose were more likely to die than were those with more episodes of severe hypoglycemia.
Data source: Further analysis of data from both DEVOTE 2 and DEVOTE 3, involving 7,637 patients with type 2 diabetes who were treated with either insulin degludec or insulin glargine.
Disclosures: The study was funded by Novo Nordisk. All presenters have received consulting fees from Novo Nordisk among other pharmaceutical companies. Two presenters (Dr. Zinman and Dr. Pieber) also disclosed receiving research support from the company.
Many years on metformin linked to anemia risk
LISBON – People with type 2 diabetes who take metformin for many years are more likely to develop anemia than are those who do not, according to the results of a large analysis of data from an observational, population-based study with 20 years of follow-up.
“Metformin treatment was associated with a 6% higher risk of anemia for every cumulative year of metformin exposure,” Louise Donnelly, PhD, and her associates reported in a poster presentation at the annual meeting of the European Association for the Study of Diabetes.
In an interview, Dr. Donnelly, a postdoctoral research assistant at the University of Dundee (Scotland), explained why they looked at the use of metformin and anemia risk in people with type 2 diabetes.
“The Diabetes Prevention Program (DPP) study showed that long-term metformin use in individuals with impaired glucose tolerance was associated with an increased risk of anemia, and this was independent of vitamin B12 status,” she said (J Clin Endocrinol Metab. 2016;101:1754-61). “Anemia is a common finding in people with type 2 diabetes, but the impact of long-term metformin use on anemia hasn’t been studied.”
Dr. Donnelly and her associates obtained detailed information on metformin prescribing and hematology measures from electronic patient medical records from the Genetics of Diabetes Audit and Research in Tayside and Scotland (GoDARTS) cohort, based in Scotland. This database contains information on individuals with type 2 diabetes and matching controls and is available to researchers worldwide.
For the analysis, the team looked for people diagnosed from 1996 onward who had a baseline hemoglobin measurement. Of 6,440 individuals with type 2 diabetes in the GoDARTS cohort, just over half had a hemoglobin measurement.
“We used a definition of ‘moderate’ anemia and we excluded patients with mild anemia or worse at diabetes diagnosis,” Dr. Donnelly observed. Anemia was considered to be a hemoglobin level of less than 12 g/dL in women and less than 13 g/dL in men. In all, 280 individuals with anemia were excluded from further analysis as the aim was to follow people until they developed anemia, died, left the area, or until the end of the follow-up period, which was set at September 30, 2015. A discrete-time failure analysis was used to model the effect of cumulative metformin exposure on anemia risk.
After a median follow-up of 8 years and a median number of 11 hemoglobin measurements per patient, 2,487 study subjects (71%) had some exposure to metformin and 1,458 of the whole sample (41.8%) had become anemic. Of those who developed anemia, 745 (51%) were current metformin users, 194 (13%) were former users, and 519 (36%) had never taken metformin.
“Cumulative metformin use was independently associated with an increased risk of anemia,” Dr. Donnelly noted (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.02-1.09; P = .0006). This association was not seen when they examined the data based on sulfonylurea use (OR 1.0; 95% CI 0.97-1.04, P = .8), she added.
“Anemia risk was higher with age at diagnosis, duration of diabetes, lower hemoglobin at baseline, and lower eGFR [estimated glomerular filtration rate],” she observed. ORs for first anemia event were 1.03 (95% CI, 1.02-1.04) for every year of increasing age, 1.05 (95% CI, 1.03-1.08) for every additional year since diabetes diagnosis, 0.70 (95% CI, 0.66-0.74) per 1 g/dL of hemoglobin at diagnosis, and eGFR 0.98 (95% CI, 0.98-1.01) per additional 1 mL/min per 1.732 (P less than .0001 for all).
Why cumulative metformin use is associated with an increased of anemia is unclear, however, and Dr. Donnelly noted that this needs further investigation. “We do have data from two other clinical trials now, showing similar results, and maybe through those data we might be able to untangle it.”
The team does not think the anemia is related to B12 deficiency, however, as people who developed anemia while taking metformin were more likely to develop microcytic (12% vs. 7.3%) than macrocytic (7.6% vs. 12.3%), anemia, compared with people with anemia who were not exposed to metformin (P less than .0001).
“In terms of mechanism, we can only conjecture,” Ewan Pearson, MB, senior author of the study and professor of medicine at the University of Dundee, said during a discussion at the poster presentation. “It is important to stress that metformin is a great drug and we shouldn’t stop it because of a potentially increased risk of anemia.”
The Medical Research Council supported the work. Dr. Donnelly reported having no financial disclosures.
LISBON – People with type 2 diabetes who take metformin for many years are more likely to develop anemia than are those who do not, according to the results of a large analysis of data from an observational, population-based study with 20 years of follow-up.
“Metformin treatment was associated with a 6% higher risk of anemia for every cumulative year of metformin exposure,” Louise Donnelly, PhD, and her associates reported in a poster presentation at the annual meeting of the European Association for the Study of Diabetes.
In an interview, Dr. Donnelly, a postdoctoral research assistant at the University of Dundee (Scotland), explained why they looked at the use of metformin and anemia risk in people with type 2 diabetes.
“The Diabetes Prevention Program (DPP) study showed that long-term metformin use in individuals with impaired glucose tolerance was associated with an increased risk of anemia, and this was independent of vitamin B12 status,” she said (J Clin Endocrinol Metab. 2016;101:1754-61). “Anemia is a common finding in people with type 2 diabetes, but the impact of long-term metformin use on anemia hasn’t been studied.”
Dr. Donnelly and her associates obtained detailed information on metformin prescribing and hematology measures from electronic patient medical records from the Genetics of Diabetes Audit and Research in Tayside and Scotland (GoDARTS) cohort, based in Scotland. This database contains information on individuals with type 2 diabetes and matching controls and is available to researchers worldwide.
For the analysis, the team looked for people diagnosed from 1996 onward who had a baseline hemoglobin measurement. Of 6,440 individuals with type 2 diabetes in the GoDARTS cohort, just over half had a hemoglobin measurement.
“We used a definition of ‘moderate’ anemia and we excluded patients with mild anemia or worse at diabetes diagnosis,” Dr. Donnelly observed. Anemia was considered to be a hemoglobin level of less than 12 g/dL in women and less than 13 g/dL in men. In all, 280 individuals with anemia were excluded from further analysis as the aim was to follow people until they developed anemia, died, left the area, or until the end of the follow-up period, which was set at September 30, 2015. A discrete-time failure analysis was used to model the effect of cumulative metformin exposure on anemia risk.
After a median follow-up of 8 years and a median number of 11 hemoglobin measurements per patient, 2,487 study subjects (71%) had some exposure to metformin and 1,458 of the whole sample (41.8%) had become anemic. Of those who developed anemia, 745 (51%) were current metformin users, 194 (13%) were former users, and 519 (36%) had never taken metformin.
“Cumulative metformin use was independently associated with an increased risk of anemia,” Dr. Donnelly noted (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.02-1.09; P = .0006). This association was not seen when they examined the data based on sulfonylurea use (OR 1.0; 95% CI 0.97-1.04, P = .8), she added.
“Anemia risk was higher with age at diagnosis, duration of diabetes, lower hemoglobin at baseline, and lower eGFR [estimated glomerular filtration rate],” she observed. ORs for first anemia event were 1.03 (95% CI, 1.02-1.04) for every year of increasing age, 1.05 (95% CI, 1.03-1.08) for every additional year since diabetes diagnosis, 0.70 (95% CI, 0.66-0.74) per 1 g/dL of hemoglobin at diagnosis, and eGFR 0.98 (95% CI, 0.98-1.01) per additional 1 mL/min per 1.732 (P less than .0001 for all).
Why cumulative metformin use is associated with an increased of anemia is unclear, however, and Dr. Donnelly noted that this needs further investigation. “We do have data from two other clinical trials now, showing similar results, and maybe through those data we might be able to untangle it.”
The team does not think the anemia is related to B12 deficiency, however, as people who developed anemia while taking metformin were more likely to develop microcytic (12% vs. 7.3%) than macrocytic (7.6% vs. 12.3%), anemia, compared with people with anemia who were not exposed to metformin (P less than .0001).
“In terms of mechanism, we can only conjecture,” Ewan Pearson, MB, senior author of the study and professor of medicine at the University of Dundee, said during a discussion at the poster presentation. “It is important to stress that metformin is a great drug and we shouldn’t stop it because of a potentially increased risk of anemia.”
The Medical Research Council supported the work. Dr. Donnelly reported having no financial disclosures.
LISBON – People with type 2 diabetes who take metformin for many years are more likely to develop anemia than are those who do not, according to the results of a large analysis of data from an observational, population-based study with 20 years of follow-up.
“Metformin treatment was associated with a 6% higher risk of anemia for every cumulative year of metformin exposure,” Louise Donnelly, PhD, and her associates reported in a poster presentation at the annual meeting of the European Association for the Study of Diabetes.
In an interview, Dr. Donnelly, a postdoctoral research assistant at the University of Dundee (Scotland), explained why they looked at the use of metformin and anemia risk in people with type 2 diabetes.
“The Diabetes Prevention Program (DPP) study showed that long-term metformin use in individuals with impaired glucose tolerance was associated with an increased risk of anemia, and this was independent of vitamin B12 status,” she said (J Clin Endocrinol Metab. 2016;101:1754-61). “Anemia is a common finding in people with type 2 diabetes, but the impact of long-term metformin use on anemia hasn’t been studied.”
Dr. Donnelly and her associates obtained detailed information on metformin prescribing and hematology measures from electronic patient medical records from the Genetics of Diabetes Audit and Research in Tayside and Scotland (GoDARTS) cohort, based in Scotland. This database contains information on individuals with type 2 diabetes and matching controls and is available to researchers worldwide.
For the analysis, the team looked for people diagnosed from 1996 onward who had a baseline hemoglobin measurement. Of 6,440 individuals with type 2 diabetes in the GoDARTS cohort, just over half had a hemoglobin measurement.
“We used a definition of ‘moderate’ anemia and we excluded patients with mild anemia or worse at diabetes diagnosis,” Dr. Donnelly observed. Anemia was considered to be a hemoglobin level of less than 12 g/dL in women and less than 13 g/dL in men. In all, 280 individuals with anemia were excluded from further analysis as the aim was to follow people until they developed anemia, died, left the area, or until the end of the follow-up period, which was set at September 30, 2015. A discrete-time failure analysis was used to model the effect of cumulative metformin exposure on anemia risk.
After a median follow-up of 8 years and a median number of 11 hemoglobin measurements per patient, 2,487 study subjects (71%) had some exposure to metformin and 1,458 of the whole sample (41.8%) had become anemic. Of those who developed anemia, 745 (51%) were current metformin users, 194 (13%) were former users, and 519 (36%) had never taken metformin.
“Cumulative metformin use was independently associated with an increased risk of anemia,” Dr. Donnelly noted (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.02-1.09; P = .0006). This association was not seen when they examined the data based on sulfonylurea use (OR 1.0; 95% CI 0.97-1.04, P = .8), she added.
“Anemia risk was higher with age at diagnosis, duration of diabetes, lower hemoglobin at baseline, and lower eGFR [estimated glomerular filtration rate],” she observed. ORs for first anemia event were 1.03 (95% CI, 1.02-1.04) for every year of increasing age, 1.05 (95% CI, 1.03-1.08) for every additional year since diabetes diagnosis, 0.70 (95% CI, 0.66-0.74) per 1 g/dL of hemoglobin at diagnosis, and eGFR 0.98 (95% CI, 0.98-1.01) per additional 1 mL/min per 1.732 (P less than .0001 for all).
Why cumulative metformin use is associated with an increased of anemia is unclear, however, and Dr. Donnelly noted that this needs further investigation. “We do have data from two other clinical trials now, showing similar results, and maybe through those data we might be able to untangle it.”
The team does not think the anemia is related to B12 deficiency, however, as people who developed anemia while taking metformin were more likely to develop microcytic (12% vs. 7.3%) than macrocytic (7.6% vs. 12.3%), anemia, compared with people with anemia who were not exposed to metformin (P less than .0001).
“In terms of mechanism, we can only conjecture,” Ewan Pearson, MB, senior author of the study and professor of medicine at the University of Dundee, said during a discussion at the poster presentation. “It is important to stress that metformin is a great drug and we shouldn’t stop it because of a potentially increased risk of anemia.”
The Medical Research Council supported the work. Dr. Donnelly reported having no financial disclosures.
AT EASD 2017
Key clinical point: Cumulative metformin use was associated with an increased risk for anemia in patients with type 2 diabetes.
Major finding: For every additional year of metformin use, there was a 6% increase in the risk for anemia.
Data source: Data analysis of 3,435 individuals with type 2 diabetes who participated in a large observational, population-based study with almost 20 years of follow-up.
Disclosures: The Medical Research Council supported the work. Dr. Donnelly reported having no financial disclosures.