Diabetes Hub

 

The etiology of chronic pain after bariatric surgery can be difficult to pinpoint, but diagnostic laparoscopy can detect causes in about half of patients, findings from a small study have shown.

In an investigation conducted by Mohammed Alsulaimy, MD, a surgeon at the Bariatric and Metabolic Institute at the Cleveland Clinic, and his colleagues, 35 patients underwent diagnostic laparoscopy (DL) to identify the causes of their chronic abdominal pain after bariatric surgery. Patients included in the study had a history of abdominal pain lasting longer than 30 days after their bariatric procedure, a negative CT scan of their abdomen and pelvis, a gallstone-negative abdominal ultrasound, and an upper GI endoscopy with no abnormalities. Researchers collected patient data including age, gender, body, weight, and body mass index, type of previous bariatric procedure, and time between surgery and onset of pain.

Artem_Furman/Thinkstock

These patients presented with abdominal pain a median of 26 months after surgery, although nine patients began to have abdominal pain within the first year (Obes Surg. 2017 Aug;27[8]:1924-8).

The results of DL were either positive (presence detected of pathology or injury) or negative (no disease or injury detected).

Twenty patients (57%) had positive findings on DL including the presence of adhesions, chronic cholecystitis, mesenteric defect, internal hernia, and necrotic omentum, and of this group, 43% had treatment that led to improvement of pain symptoms. Only 1 of the 15 patients with negative DL findings had eventual improvement of their pain symptoms. Most patients with negative DL findings had persistent abdominal pain, possibly because of nonorganic causes and were referred to the chronic pain management service, the investigators wrote.

“About 40% of patients who undergo DL and 70% of patients with positive findings on DL experience significant symptom improvement,” the investigators said. “This study highlights the importance of offering DL as both a diagnostic and therapeutic tool in post–bariatric surgery patients with chronic abdominal of unknown etiology.”

The investigators had no relevant financial disclosures to report.

[email protected]

 

The etiology of chronic pain after bariatric surgery can be difficult to pinpoint, but diagnostic laparoscopy can detect causes in about half of patients, findings from a small study have shown.

In an investigation conducted by Mohammed Alsulaimy, MD, a surgeon at the Bariatric and Metabolic Institute at the Cleveland Clinic, and his colleagues, 35 patients underwent diagnostic laparoscopy (DL) to identify the causes of their chronic abdominal pain after bariatric surgery. Patients included in the study had a history of abdominal pain lasting longer than 30 days after their bariatric procedure, a negative CT scan of their abdomen and pelvis, a gallstone-negative abdominal ultrasound, and an upper GI endoscopy with no abnormalities. Researchers collected patient data including age, gender, body, weight, and body mass index, type of previous bariatric procedure, and time between surgery and onset of pain.

Artem_Furman/Thinkstock

These patients presented with abdominal pain a median of 26 months after surgery, although nine patients began to have abdominal pain within the first year (Obes Surg. 2017 Aug;27[8]:1924-8).

The results of DL were either positive (presence detected of pathology or injury) or negative (no disease or injury detected).

Twenty patients (57%) had positive findings on DL including the presence of adhesions, chronic cholecystitis, mesenteric defect, internal hernia, and necrotic omentum, and of this group, 43% had treatment that led to improvement of pain symptoms. Only 1 of the 15 patients with negative DL findings had eventual improvement of their pain symptoms. Most patients with negative DL findings had persistent abdominal pain, possibly because of nonorganic causes and were referred to the chronic pain management service, the investigators wrote.

“About 40% of patients who undergo DL and 70% of patients with positive findings on DL experience significant symptom improvement,” the investigators said. “This study highlights the importance of offering DL as both a diagnostic and therapeutic tool in post–bariatric surgery patients with chronic abdominal of unknown etiology.”

The investigators had no relevant financial disclosures to report.

[email protected]

 

The etiology of chronic pain after bariatric surgery can be difficult to pinpoint, but diagnostic laparoscopy can detect causes in about half of patients, findings from a small study have shown.

In an investigation conducted by Mohammed Alsulaimy, MD, a surgeon at the Bariatric and Metabolic Institute at the Cleveland Clinic, and his colleagues, 35 patients underwent diagnostic laparoscopy (DL) to identify the causes of their chronic abdominal pain after bariatric surgery. Patients included in the study had a history of abdominal pain lasting longer than 30 days after their bariatric procedure, a negative CT scan of their abdomen and pelvis, a gallstone-negative abdominal ultrasound, and an upper GI endoscopy with no abnormalities. Researchers collected patient data including age, gender, body, weight, and body mass index, type of previous bariatric procedure, and time between surgery and onset of pain.

Artem_Furman/Thinkstock

These patients presented with abdominal pain a median of 26 months after surgery, although nine patients began to have abdominal pain within the first year (Obes Surg. 2017 Aug;27[8]:1924-8).

The results of DL were either positive (presence detected of pathology or injury) or negative (no disease or injury detected).

Twenty patients (57%) had positive findings on DL including the presence of adhesions, chronic cholecystitis, mesenteric defect, internal hernia, and necrotic omentum, and of this group, 43% had treatment that led to improvement of pain symptoms. Only 1 of the 15 patients with negative DL findings had eventual improvement of their pain symptoms. Most patients with negative DL findings had persistent abdominal pain, possibly because of nonorganic causes and were referred to the chronic pain management service, the investigators wrote.

“About 40% of patients who undergo DL and 70% of patients with positive findings on DL experience significant symptom improvement,” the investigators said. “This study highlights the importance of offering DL as both a diagnostic and therapeutic tool in post–bariatric surgery patients with chronic abdominal of unknown etiology.”

The investigators had no relevant financial disclosures to report.

[email protected]

 

Severely obese individuals in the United States who underwent Roux-en-Y gastric bypass (RYGB) averaged a 27% weight loss 12 years later, with only a 3% incidence of type 2 diabetes mellitus and a 51% rate of diabetes remission, according to the results of a large multicenter observational prospective study.

In striking contrast, patients who did not undergo bariatric surgery averaged a 1%-2% weight loss at 12 years, a 26% incidence of diabetes, and only a 5%-10% rate of diabetes remission, said Ted D. Adams, PhD, of the University of Utah, Salt Lake City, and his associates. RYGB surgery also conferred substantial and statistically significant improvements long-term improvements in systolic hypertension and lipid levels, the researchers reported in the New England Journal of Medicine (2017 Sep 20. doi: 10.1056/NEJMoa1700459).

Few prospective studies have tracked long-term outcomes after bariatric surgery. Among 1,156 participants in this study, 418 patients underwent RYGB, 417 individuals sought but did not undergo surgery – mainly for insurance reasons – and 321 individuals did not seek surgery. Participants were mostly females in their 40s or 50s at baseline, and typically weighed 120 kg-130 kg.

“The follow-up rate exceeded 90% at 12 years,” the researchers wrote. Two years after undergoing Roux-en-Y gastric bypass, patients had lost an average of 45 kg (95% confidence interval, 43-47 kg). By postoperative year 6, they had regained an average of 9 kg (average loss from baseline, 36 kg; 95% CI, 34-39 kg). But they typically gained only about 1.3 kg more between years 6 and 12, and they had about a 92% lower odds of developing diabetes mellitus, compared with individuals who did not undergo bariatric surgery (odds ratio, 0.08; P less than .001). “Remission of type 2 diabetes was much more likely if the Roux-en-Y gastric bypass occurred before [patients began] treatment with insulin, presumably owing to the ability of partially viable beta cells to improve their function,” the researchers noted.

Funders included the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center for Research Resources, Weill Cornell Medicine, and Intermountain Healthcare. Dr. Adams reported having no relevant conflicts of interest. One coinvestigator disclosed royalties from licensing a questionnaire on weight loss and quality of life, and another coinvestigator disclosed fees for services rendered during a trial of an intragastric balloon. The remaining researchers had no relevant disclosures.

 

Severely obese individuals in the United States who underwent Roux-en-Y gastric bypass (RYGB) averaged a 27% weight loss 12 years later, with only a 3% incidence of type 2 diabetes mellitus and a 51% rate of diabetes remission, according to the results of a large multicenter observational prospective study.

In striking contrast, patients who did not undergo bariatric surgery averaged a 1%-2% weight loss at 12 years, a 26% incidence of diabetes, and only a 5%-10% rate of diabetes remission, said Ted D. Adams, PhD, of the University of Utah, Salt Lake City, and his associates. RYGB surgery also conferred substantial and statistically significant improvements long-term improvements in systolic hypertension and lipid levels, the researchers reported in the New England Journal of Medicine (2017 Sep 20. doi: 10.1056/NEJMoa1700459).

Few prospective studies have tracked long-term outcomes after bariatric surgery. Among 1,156 participants in this study, 418 patients underwent RYGB, 417 individuals sought but did not undergo surgery – mainly for insurance reasons – and 321 individuals did not seek surgery. Participants were mostly females in their 40s or 50s at baseline, and typically weighed 120 kg-130 kg.

“The follow-up rate exceeded 90% at 12 years,” the researchers wrote. Two years after undergoing Roux-en-Y gastric bypass, patients had lost an average of 45 kg (95% confidence interval, 43-47 kg). By postoperative year 6, they had regained an average of 9 kg (average loss from baseline, 36 kg; 95% CI, 34-39 kg). But they typically gained only about 1.3 kg more between years 6 and 12, and they had about a 92% lower odds of developing diabetes mellitus, compared with individuals who did not undergo bariatric surgery (odds ratio, 0.08; P less than .001). “Remission of type 2 diabetes was much more likely if the Roux-en-Y gastric bypass occurred before [patients began] treatment with insulin, presumably owing to the ability of partially viable beta cells to improve their function,” the researchers noted.

Funders included the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center for Research Resources, Weill Cornell Medicine, and Intermountain Healthcare. Dr. Adams reported having no relevant conflicts of interest. One coinvestigator disclosed royalties from licensing a questionnaire on weight loss and quality of life, and another coinvestigator disclosed fees for services rendered during a trial of an intragastric balloon. The remaining researchers had no relevant disclosures.

 

Severely obese individuals in the United States who underwent Roux-en-Y gastric bypass (RYGB) averaged a 27% weight loss 12 years later, with only a 3% incidence of type 2 diabetes mellitus and a 51% rate of diabetes remission, according to the results of a large multicenter observational prospective study.

In striking contrast, patients who did not undergo bariatric surgery averaged a 1%-2% weight loss at 12 years, a 26% incidence of diabetes, and only a 5%-10% rate of diabetes remission, said Ted D. Adams, PhD, of the University of Utah, Salt Lake City, and his associates. RYGB surgery also conferred substantial and statistically significant improvements long-term improvements in systolic hypertension and lipid levels, the researchers reported in the New England Journal of Medicine (2017 Sep 20. doi: 10.1056/NEJMoa1700459).

Few prospective studies have tracked long-term outcomes after bariatric surgery. Among 1,156 participants in this study, 418 patients underwent RYGB, 417 individuals sought but did not undergo surgery – mainly for insurance reasons – and 321 individuals did not seek surgery. Participants were mostly females in their 40s or 50s at baseline, and typically weighed 120 kg-130 kg.

“The follow-up rate exceeded 90% at 12 years,” the researchers wrote. Two years after undergoing Roux-en-Y gastric bypass, patients had lost an average of 45 kg (95% confidence interval, 43-47 kg). By postoperative year 6, they had regained an average of 9 kg (average loss from baseline, 36 kg; 95% CI, 34-39 kg). But they typically gained only about 1.3 kg more between years 6 and 12, and they had about a 92% lower odds of developing diabetes mellitus, compared with individuals who did not undergo bariatric surgery (odds ratio, 0.08; P less than .001). “Remission of type 2 diabetes was much more likely if the Roux-en-Y gastric bypass occurred before [patients began] treatment with insulin, presumably owing to the ability of partially viable beta cells to improve their function,” the researchers noted.

Funders included the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center for Research Resources, Weill Cornell Medicine, and Intermountain Healthcare. Dr. Adams reported having no relevant conflicts of interest. One coinvestigator disclosed royalties from licensing a questionnaire on weight loss and quality of life, and another coinvestigator disclosed fees for services rendered during a trial of an intragastric balloon. The remaining researchers had no relevant disclosures.

LISBON – Pregnant women with type 1 diabetes mellitus should be offered continuous glucose monitoring, according to the investigators of a prospective, multicenter, randomized, controlled study who found that it improved a number of neonatal outcomes.

In the open-label Continuous Glucose Monitoring in Pregnant Women with Type 1 Diabetes(CONCEPTT) study, infants born to mothers who had used continuous glucose monitoring (CGM) versus those who had not had a 49% lower chance of being large for gestational age (53% vs. 69%, odds ratio [OR] 0.51, P = .0210) and were 52% less likely to need neonatal intensive care lasting for longer than 24 hours (27% vs. 43%, OR 0.48, P = .0157).

Neonates born to mothers who used CGM during their pregnancy were also less likely to experience hypoglycemia (15% vs. 28%, OR 0.45, P = .0250) and were able to leave the hospital with their mother 1 day earlier (P = .0091) than those born to mothers who did not use CGM.However, these were secondary outcomes of the study, which first looked at how CGM affected the glycemic profile of the mother.“To the best of our knowledge, this is the first trial to demonstrate a benefit of CGM on health outcomes beyond glucose control,” Helen Murphy, MD, one of the CONCEPTT trial’s two principal investigators, said at the annual meeting of the European Association for the Study of Diabetes.

Dr. Murphy, who is an honorary consultant physician at Cambridge (England) University Hospitals NHS Foundation Trust and at Norfolk & Norwich NHS Foundation Trust, observed that the improved neonatal outcomes were likely a result of reduced exposure to maternal hyperglycemia.

“We would suggest, on the back of these data, that CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy during the first trimester,” Dr. Murphy said, adding that results of the study were simultaneously published online in the Lancet (2017 Sept. 15. doi. 10.1016/S0140-6736(17)32400-5).

“The CONCEPTT study will change the future for pregnant women with diabetes,” commented Elisabeth Mathiesen, MD, who was the EASD’s invited discussant for the study, and who congratulated the investigators for “a well performed study” and being “brave,” as “performing a RCT [randomized controlled trial] in pregnancy is not easy”.

Satish Garg, MD, and Sarit Polsky, MD, of the Barbara Davis Center for Diabetes at the University of Colorado, Denver, agreed in an editorial (Lancet 2017; Sept. 12. doi: 10.1016/S0140-6736(17)32449-2) accompanying the published article that the study findings were clinically important.
 

“We believe that the CONCEPTT results support CGM use during pregnancy for all women with type 1 diabetes,” they wrote, adding that the mother’s “time in [glycated hemoglobin, HbA_1C] range might become an important measure in pregnancies with type 1 diabetes.”

Dr. Garg and Dr. Polsky also suggested that endocrine and obstetric medical societies take note and perhaps revise accordingly their guidelines on the use of CGM during pregnancy in diabetic women.

CONCEPTT involved 325 women with type 1 diabetes; 215 were pregnant at the time of enrollment, and 110 were planning on becoming pregnant in the near future.

Co-principal investigator Denice Feig, MD, of Sinai Health System in Toronto, explained that women were eligible for inclusion in the trial if they had type 1 diabetes for at least 1 year, were aged between 18 and 40 years, and had been using daily insulin delivered by either an insulin pump or multiple daily injections (MDI). At enrollment, the participants’ insulin regimen had to been stable for at least 4 weeks before randomization to CGM with capillary glucose monitoring or capillary glucose monitoring alone and their glycemic control had to be suboptimal.

Two groups of women were studied: a “pre-pregnancy group” of women who were planning on pregnancy and wanted to optimize their glycemic control before conception, and a “pregnancy group” of women in their first trimester (less than 14 weeks’ gestation) who were due to have a live, singleton birth as confirmed by ultrasound.

The primary outcome of the trial was the change in HbA_1C from baseline to 34 weeks, with pre-specified secondary outcomes of various CGM measures, neoneonatal outcomes, and patient-reported outcomes.

Pregnant women using CGM had lower HbA_1C levels during the trial than women who did not have CGM monitoring, although the difference was small (–0.19%, P = .0207).

The use of CGM was associated with more time spent in target HbA1_C range (68% of women using CMG vs. 61% of those not using CGM, P = .0034), with less time being hyperglycemic (27% vs. 37%, P = .0279) and comparable rates of hypoglycemia (17 vs. 21 episodes) and time spent being hypoglycemic (2% vs. 4%, P = .10).“The CGM effects were very comparable among insulin pump and MDI users and across 31 international sites,” Dr. Murphy summarized, although she noted that there was no consistent benefit of using CGM seen in women who were planning a pregnancy. Dr. Feig noted that the strengths of the study were the large sample size and that CGM was used continuously from the first trimester until delivery. Women using both pumps and MDI were included at multiple centers and countries, and HbA1_C was centrally assessed, with detailed CGM measures used in an exclusively type 1 diabetes population.“Of note, one needed to treat only six women with CGM to prevent one episode of large for gestational age,” Dr. Feig reported. “One needed to treat only eight women to prevent one neonatal hypoglycemia, and six women to prevent one NICU [neonatal intensive care unit] admission over 24 hours.”

There were some limitations, of course, including: around 20% of women had missing data on their HbA_1C level; women using CGM also made more unscheduled visits to their health care providers although there are no data on the frequency of self-monitoring of blood glucose or frequency of insulin bolus dosing; and the study was open label.

In her independent précis of the trial, Dr. Mathiesen, professor of endocrinology and chief physician managing pregnant women with diabetes at the Rigshospitalet University Hospital in Copenhagen, noted that there were some other downsides to using CGM in the study.

Dr. Mathiesen said that “80% of women had self-reported problems with using the sensor, half of them experienced skin problems, and approximately 30% of women used the sensor less than 75% of the time, so not everybody was very keen on the sensor” and “using sensors deserves extra effort and time from the caregivers, especially from the nurses.” Dr. Mathiesen queried the cost of using CGM in all women with type 1 diabetes during their pregnancy; the cost of CGM use in 20 pregnant women, for example, was the equivalent of employing one nurse in Denmark, she suggested. That said, Dr. Mathiesen acknowledged that there was now evidence-based data to consider using CGM in selected pregnant women with type 1 diabetes.

The CONCEPTT study was funded by the Juvenile Diabetes Research Foundation, the Canadian Clinical Trial Network, the National Institute for Health Research, the Center for Mother, Infant, and Child Research, and the Jaeb Center for Health Research. Medtronic also supported the study by providing the CGM sensors and systems at a reduced cost. Dr. Feig declared she had no competing interests. Dr. Murphy disclosed sitting on an advisory board for Medtronic and receiving personal fees from Novo Nordisk and Roche, unrelated to the current study. Dr. Mathiesen was the invited EASD independent commentator for the trial and did not give any disclosures. Dr. Garg has received advisory board consulting fees and research grants from Medtronic and several other pharmaceutical companies specializing in diabetes care. Dr. Polsky has received research funding from DexCom for diabetes device use in patients with diabetes paid directly to the University of Denver.

LISBON – Pregnant women with type 1 diabetes mellitus should be offered continuous glucose monitoring, according to the investigators of a prospective, multicenter, randomized, controlled study who found that it improved a number of neonatal outcomes.

In the open-label Continuous Glucose Monitoring in Pregnant Women with Type 1 Diabetes(CONCEPTT) study, infants born to mothers who had used continuous glucose monitoring (CGM) versus those who had not had a 49% lower chance of being large for gestational age (53% vs. 69%, odds ratio [OR] 0.51, P = .0210) and were 52% less likely to need neonatal intensive care lasting for longer than 24 hours (27% vs. 43%, OR 0.48, P = .0157).

Neonates born to mothers who used CGM during their pregnancy were also less likely to experience hypoglycemia (15% vs. 28%, OR 0.45, P = .0250) and were able to leave the hospital with their mother 1 day earlier (P = .0091) than those born to mothers who did not use CGM.However, these were secondary outcomes of the study, which first looked at how CGM affected the glycemic profile of the mother.“To the best of our knowledge, this is the first trial to demonstrate a benefit of CGM on health outcomes beyond glucose control,” Helen Murphy, MD, one of the CONCEPTT trial’s two principal investigators, said at the annual meeting of the European Association for the Study of Diabetes.

Dr. Murphy, who is an honorary consultant physician at Cambridge (England) University Hospitals NHS Foundation Trust and at Norfolk & Norwich NHS Foundation Trust, observed that the improved neonatal outcomes were likely a result of reduced exposure to maternal hyperglycemia.

“We would suggest, on the back of these data, that CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy during the first trimester,” Dr. Murphy said, adding that results of the study were simultaneously published online in the Lancet (2017 Sept. 15. doi. 10.1016/S0140-6736(17)32400-5).

“The CONCEPTT study will change the future for pregnant women with diabetes,” commented Elisabeth Mathiesen, MD, who was the EASD’s invited discussant for the study, and who congratulated the investigators for “a well performed study” and being “brave,” as “performing a RCT [randomized controlled trial] in pregnancy is not easy”.

Satish Garg, MD, and Sarit Polsky, MD, of the Barbara Davis Center for Diabetes at the University of Colorado, Denver, agreed in an editorial (Lancet 2017; Sept. 12. doi: 10.1016/S0140-6736(17)32449-2) accompanying the published article that the study findings were clinically important.
 

“We believe that the CONCEPTT results support CGM use during pregnancy for all women with type 1 diabetes,” they wrote, adding that the mother’s “time in [glycated hemoglobin, HbA_1C] range might become an important measure in pregnancies with type 1 diabetes.”

Dr. Garg and Dr. Polsky also suggested that endocrine and obstetric medical societies take note and perhaps revise accordingly their guidelines on the use of CGM during pregnancy in diabetic women.

CONCEPTT involved 325 women with type 1 diabetes; 215 were pregnant at the time of enrollment, and 110 were planning on becoming pregnant in the near future.

Co-principal investigator Denice Feig, MD, of Sinai Health System in Toronto, explained that women were eligible for inclusion in the trial if they had type 1 diabetes for at least 1 year, were aged between 18 and 40 years, and had been using daily insulin delivered by either an insulin pump or multiple daily injections (MDI). At enrollment, the participants’ insulin regimen had to been stable for at least 4 weeks before randomization to CGM with capillary glucose monitoring or capillary glucose monitoring alone and their glycemic control had to be suboptimal.

Two groups of women were studied: a “pre-pregnancy group” of women who were planning on pregnancy and wanted to optimize their glycemic control before conception, and a “pregnancy group” of women in their first trimester (less than 14 weeks’ gestation) who were due to have a live, singleton birth as confirmed by ultrasound.

The primary outcome of the trial was the change in HbA_1C from baseline to 34 weeks, with pre-specified secondary outcomes of various CGM measures, neoneonatal outcomes, and patient-reported outcomes.

Pregnant women using CGM had lower HbA_1C levels during the trial than women who did not have CGM monitoring, although the difference was small (–0.19%, P = .0207).

The use of CGM was associated with more time spent in target HbA1_C range (68% of women using CMG vs. 61% of those not using CGM, P = .0034), with less time being hyperglycemic (27% vs. 37%, P = .0279) and comparable rates of hypoglycemia (17 vs. 21 episodes) and time spent being hypoglycemic (2% vs. 4%, P = .10).“The CGM effects were very comparable among insulin pump and MDI users and across 31 international sites,” Dr. Murphy summarized, although she noted that there was no consistent benefit of using CGM seen in women who were planning a pregnancy. Dr. Feig noted that the strengths of the study were the large sample size and that CGM was used continuously from the first trimester until delivery. Women using both pumps and MDI were included at multiple centers and countries, and HbA1_C was centrally assessed, with detailed CGM measures used in an exclusively type 1 diabetes population.“Of note, one needed to treat only six women with CGM to prevent one episode of large for gestational age,” Dr. Feig reported. “One needed to treat only eight women to prevent one neonatal hypoglycemia, and six women to prevent one NICU [neonatal intensive care unit] admission over 24 hours.”

There were some limitations, of course, including: around 20% of women had missing data on their HbA_1C level; women using CGM also made more unscheduled visits to their health care providers although there are no data on the frequency of self-monitoring of blood glucose or frequency of insulin bolus dosing; and the study was open label.

In her independent précis of the trial, Dr. Mathiesen, professor of endocrinology and chief physician managing pregnant women with diabetes at the Rigshospitalet University Hospital in Copenhagen, noted that there were some other downsides to using CGM in the study.

Dr. Mathiesen said that “80% of women had self-reported problems with using the sensor, half of them experienced skin problems, and approximately 30% of women used the sensor less than 75% of the time, so not everybody was very keen on the sensor” and “using sensors deserves extra effort and time from the caregivers, especially from the nurses.” Dr. Mathiesen queried the cost of using CGM in all women with type 1 diabetes during their pregnancy; the cost of CGM use in 20 pregnant women, for example, was the equivalent of employing one nurse in Denmark, she suggested. That said, Dr. Mathiesen acknowledged that there was now evidence-based data to consider using CGM in selected pregnant women with type 1 diabetes.

The CONCEPTT study was funded by the Juvenile Diabetes Research Foundation, the Canadian Clinical Trial Network, the National Institute for Health Research, the Center for Mother, Infant, and Child Research, and the Jaeb Center for Health Research. Medtronic also supported the study by providing the CGM sensors and systems at a reduced cost. Dr. Feig declared she had no competing interests. Dr. Murphy disclosed sitting on an advisory board for Medtronic and receiving personal fees from Novo Nordisk and Roche, unrelated to the current study. Dr. Mathiesen was the invited EASD independent commentator for the trial and did not give any disclosures. Dr. Garg has received advisory board consulting fees and research grants from Medtronic and several other pharmaceutical companies specializing in diabetes care. Dr. Polsky has received research funding from DexCom for diabetes device use in patients with diabetes paid directly to the University of Denver.

LISBON – Pregnant women with type 1 diabetes mellitus should be offered continuous glucose monitoring, according to the investigators of a prospective, multicenter, randomized, controlled study who found that it improved a number of neonatal outcomes.

In the open-label Continuous Glucose Monitoring in Pregnant Women with Type 1 Diabetes(CONCEPTT) study, infants born to mothers who had used continuous glucose monitoring (CGM) versus those who had not had a 49% lower chance of being large for gestational age (53% vs. 69%, odds ratio [OR] 0.51, P = .0210) and were 52% less likely to need neonatal intensive care lasting for longer than 24 hours (27% vs. 43%, OR 0.48, P = .0157).

Neonates born to mothers who used CGM during their pregnancy were also less likely to experience hypoglycemia (15% vs. 28%, OR 0.45, P = .0250) and were able to leave the hospital with their mother 1 day earlier (P = .0091) than those born to mothers who did not use CGM.However, these were secondary outcomes of the study, which first looked at how CGM affected the glycemic profile of the mother.“To the best of our knowledge, this is the first trial to demonstrate a benefit of CGM on health outcomes beyond glucose control,” Helen Murphy, MD, one of the CONCEPTT trial’s two principal investigators, said at the annual meeting of the European Association for the Study of Diabetes.

Dr. Murphy, who is an honorary consultant physician at Cambridge (England) University Hospitals NHS Foundation Trust and at Norfolk & Norwich NHS Foundation Trust, observed that the improved neonatal outcomes were likely a result of reduced exposure to maternal hyperglycemia.

“We would suggest, on the back of these data, that CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy during the first trimester,” Dr. Murphy said, adding that results of the study were simultaneously published online in the Lancet (2017 Sept. 15. doi. 10.1016/S0140-6736(17)32400-5).

“The CONCEPTT study will change the future for pregnant women with diabetes,” commented Elisabeth Mathiesen, MD, who was the EASD’s invited discussant for the study, and who congratulated the investigators for “a well performed study” and being “brave,” as “performing a RCT [randomized controlled trial] in pregnancy is not easy”.

Satish Garg, MD, and Sarit Polsky, MD, of the Barbara Davis Center for Diabetes at the University of Colorado, Denver, agreed in an editorial (Lancet 2017; Sept. 12. doi: 10.1016/S0140-6736(17)32449-2) accompanying the published article that the study findings were clinically important.
 

“We believe that the CONCEPTT results support CGM use during pregnancy for all women with type 1 diabetes,” they wrote, adding that the mother’s “time in [glycated hemoglobin, HbA_1C] range might become an important measure in pregnancies with type 1 diabetes.”

Dr. Garg and Dr. Polsky also suggested that endocrine and obstetric medical societies take note and perhaps revise accordingly their guidelines on the use of CGM during pregnancy in diabetic women.

CONCEPTT involved 325 women with type 1 diabetes; 215 were pregnant at the time of enrollment, and 110 were planning on becoming pregnant in the near future.

Co-principal investigator Denice Feig, MD, of Sinai Health System in Toronto, explained that women were eligible for inclusion in the trial if they had type 1 diabetes for at least 1 year, were aged between 18 and 40 years, and had been using daily insulin delivered by either an insulin pump or multiple daily injections (MDI). At enrollment, the participants’ insulin regimen had to been stable for at least 4 weeks before randomization to CGM with capillary glucose monitoring or capillary glucose monitoring alone and their glycemic control had to be suboptimal.

Two groups of women were studied: a “pre-pregnancy group” of women who were planning on pregnancy and wanted to optimize their glycemic control before conception, and a “pregnancy group” of women in their first trimester (less than 14 weeks’ gestation) who were due to have a live, singleton birth as confirmed by ultrasound.

The primary outcome of the trial was the change in HbA_1C from baseline to 34 weeks, with pre-specified secondary outcomes of various CGM measures, neoneonatal outcomes, and patient-reported outcomes.

Pregnant women using CGM had lower HbA_1C levels during the trial than women who did not have CGM monitoring, although the difference was small (–0.19%, P = .0207).

The use of CGM was associated with more time spent in target HbA1_C range (68% of women using CMG vs. 61% of those not using CGM, P = .0034), with less time being hyperglycemic (27% vs. 37%, P = .0279) and comparable rates of hypoglycemia (17 vs. 21 episodes) and time spent being hypoglycemic (2% vs. 4%, P = .10).“The CGM effects were very comparable among insulin pump and MDI users and across 31 international sites,” Dr. Murphy summarized, although she noted that there was no consistent benefit of using CGM seen in women who were planning a pregnancy. Dr. Feig noted that the strengths of the study were the large sample size and that CGM was used continuously from the first trimester until delivery. Women using both pumps and MDI were included at multiple centers and countries, and HbA1_C was centrally assessed, with detailed CGM measures used in an exclusively type 1 diabetes population.“Of note, one needed to treat only six women with CGM to prevent one episode of large for gestational age,” Dr. Feig reported. “One needed to treat only eight women to prevent one neonatal hypoglycemia, and six women to prevent one NICU [neonatal intensive care unit] admission over 24 hours.”

There were some limitations, of course, including: around 20% of women had missing data on their HbA_1C level; women using CGM also made more unscheduled visits to their health care providers although there are no data on the frequency of self-monitoring of blood glucose or frequency of insulin bolus dosing; and the study was open label.

In her independent précis of the trial, Dr. Mathiesen, professor of endocrinology and chief physician managing pregnant women with diabetes at the Rigshospitalet University Hospital in Copenhagen, noted that there were some other downsides to using CGM in the study.

Dr. Mathiesen said that “80% of women had self-reported problems with using the sensor, half of them experienced skin problems, and approximately 30% of women used the sensor less than 75% of the time, so not everybody was very keen on the sensor” and “using sensors deserves extra effort and time from the caregivers, especially from the nurses.” Dr. Mathiesen queried the cost of using CGM in all women with type 1 diabetes during their pregnancy; the cost of CGM use in 20 pregnant women, for example, was the equivalent of employing one nurse in Denmark, she suggested. That said, Dr. Mathiesen acknowledged that there was now evidence-based data to consider using CGM in selected pregnant women with type 1 diabetes.

The CONCEPTT study was funded by the Juvenile Diabetes Research Foundation, the Canadian Clinical Trial Network, the National Institute for Health Research, the Center for Mother, Infant, and Child Research, and the Jaeb Center for Health Research. Medtronic also supported the study by providing the CGM sensors and systems at a reduced cost. Dr. Feig declared she had no competing interests. Dr. Murphy disclosed sitting on an advisory board for Medtronic and receiving personal fees from Novo Nordisk and Roche, unrelated to the current study. Dr. Mathiesen was the invited EASD independent commentator for the trial and did not give any disclosures. Dr. Garg has received advisory board consulting fees and research grants from Medtronic and several other pharmaceutical companies specializing in diabetes care. Dr. Polsky has received research funding from DexCom for diabetes device use in patients with diabetes paid directly to the University of Denver.

 

LISBON – Additional data released from the ODYSSEY DM clinical trials program show that the PCSK9 inhibitor alirocumab lowers lipid levels works just as well in patients with type 1 diabetes as it does in those with type 2 diabetes, plus it may have an edge over using older, add-on lipid-lowering therapies such as fibrates.

The findings were presented at the annual meeting of the European Association for the Study of Diabetes.

In one study involving 76 insulin-treated patients with T1DM, treatment with alirocumab (Praluent, Sanofi/Regeneron Pharmaceuticals) reduced low-density lipoprotein cholesterol levels by a mean of 47.8% versus placebo from baseline to week 24 (P less than .0001), the primary endpoint of the study.

Furthermore, in a separate study involving 413 patients with T2DM with mixed hyperlipidemia, alirocumab decreased levels of non–high-density lipoprotein cholesterol (non-HDL-C) by 33.3% compared with fenofibrate (P less than .0001).

These new results from the ODYSSEY DM-INSULIN and ODYSSEY DM-DYSLIPIDEMIA trials, respectively, add to those already presented this year at the annual scientific sessions of the American Diabetes Association.

Sara Freeman/Frontline Medical News

At the ADA meeting it was reported that, after 24 weeks, alirocumab therapy cut LDL-C by 49% more than placebo (P less than .0001) in insulin-treated patients with T2DM, and that non-HDL-C fell by 32.5% more compared with usual care (P less than .0001) in the lipid trial.

“We have studied two groups of high- to very-high cardiovascular risk patients with diabetes mellitus: those on insulin and those with mixed dyslipidemia in whom previously only secondary data were available,” said Stefano Del Prato, MD, who presented the lipid study. “These are dedicated studies in these specific populations,” he added.

In these high-risk diabetic populations, Dr. Del Prato, professor of endocrinology and metabolism and chief of the section of diabetes, University of Pisa, Italy, observed “alirocumab was superior in lipid-lowering efficacy compared to standard care, with no specific safety issues.”
 

Efficacy unaffected by co-administration with insulin use

Helen Colhoun, MD, AXA chair of medical informatics and life course epidemiology at the University of Edinburgh, presented the updated findings of the ODYSSEY DM-INSULIN study, which recruited 517 patients, the majority (n = 441) of whom had T2DM.

In the study, alirocumab, a monoclonal antibody that targets proprotein convertase subtilisin–kexin type 9 (PCSK9), was compared with placebo in patients with established atherosclerotic cardiovascular disease or other cardiovascular risk factors, and in whom LDL-C was 70 mg/dL (1.8 mmol/L) or higher.

The percentage change in LDL-C from baseline to week 24 was similarly reduced in T1DM and T2DM, Dr. Colhoun observed, and commensurate with data seen across the ODYSSEY phase III trials program. Of note, the majority of type 2 (80%) and type 1 (63%) patients did not need the dose of alirocumab to be increased and remained on the starting dose of 75 mg every 2 weeks.

Sara Freeman/Frontline Medical News

“It is very pleasing to see no evidence of loss of efficacy of alirocumab among people with type 1 diabetes,” Dr. Colhoun said. Despite the “modest sample size, you can see the treatment effect is highly, clinically, and statistically significant.”

The results of the ODYSSEY DM-INSULIN trial, which were published online, Sept. 14, 2017, to coincide with their presentation at the meeting, also showed that the percentage change in LDL-C over time is “well sustained” and that 70% and 76% of patients with T1DM and T2DM, respectively, can achieve an LDL-C target of less than 70 mg/dL (1.8 mmol/L) and 79% and 71% can hit a non-HDL-C target of less than 100 mg/dL (2.6 mmol/L).

Other lipid parameters – including apolipoprotein (Apo) B, total cholesterol, Lp(a), and triglycerides – were also reduced to a greater extent in patients treated with alirocumab versus those given placebo. Dr. Colhoun drew attention to the reduction in Lp(a), which dropped by 23% in patients with T1DM and by 19% in patients with T2DM, as it is an important risk factor for peripheral vascular disease, and it is not affected by statin therapy.

“What this trial has told us is that coadministering alirocumab with insulin does not adversely affect its efficacy,” said Dr. Colhoun. “There’s absolutely no evidence of alirocumab altering HbA_1c or fasting plasma glucose,” she added. There was also no affect on how patients were treated, either with insulin therapy or antihyperglycemic drugs.

Overall safety findings were “reassuring” and anti-drug antibodies were rare (2.1%) and did not affect the lipid-lowering effects of alirocumab.
 

Alirocumab beats fenofibrate as add-on lipid-lowering therapy

 

Presenting the ODYSSEY DM-DYSLIPIDEMIA data, which involved patients with T2DM, Dr. Del Prato observed that alirocumab was “generally well tolerated” and did not affect HbA_1c or fasting plasma glucose levels.

He presented new data from a prespecified analysis that looked at the subgroup of 72 patients who were randomized into an alirocumab (n = 48) or fenofibrate (n = 24) as usual care arm. Dr. Del Prato reminded the audience that the choice of usual treatment was decided by the study investigators prior to randomizing patients, and that other usual care treatments included in the study were ezetimibe, omega-3 fatty acids, nicotinic acid, or no lipid-lowering therapy.

As in the insulin study, the majority (63.6%) of patients treated with alirocumab remained on the starting dose of 75 mg every 2 weeks and did not need up-titration.

Changes in the percentage of non-HDL-C from baseline over time were greater in the alirocumab group than in the usual care group, both in the overall population and in the fenofibrate subanalysis.

Higher percentages of patients treated with alirocumab achieved non-HDL-C compared with those given usual care (66.9% vs. 17.7% in overall population, 65.2% vs. 10.1% in fenofibrate sub-analysis) and LDL-C (70.8% vs. 16.3% and 71.9% vs. 17.5%, respectively) goals at week 24.

Alirocumab also significantly reduced levels of Apo B, total cholesterol, and Lp(a) versus the overall usual care group and also versus the fenofibrate usual care group, Dr. Del Prato said.

Taking the two studies together, he concluded: “These data support alirocumab as a treatment option in people with diabetes mellitus and hypercholesterolemia despite maximally tolerated statins,” Dr. Del Prato said.
 

Will the lipid-benefits translate into improved cardiovascular outcomes?

The question now is whether the lipid-lowering effects of alirocumab in patients with diabetes will translate into improved cardiovascular outcomes in patients with diabetes.

The results of the ODYSSEY OUTCOMES trial, which is evaluating cardiovascular outcomes during treatment with alirocumab after an acute coronary syndrome, are expected next year. While the trial is not being conducted specifically in patients with diabetes, it is expected that there will be subpopulations of T1DM and T2DM patients included.

Cardiovascular outcomes data on the PCSK9 inhibitor, evolocumab (Repatha, Amgen) in the FOURIER trial were published in March (N Engl J Med 2017;376:1713-22) and provide some evidence that a reduction in major cardiovascular events may be possible with these agents.

Providing independent comment on the study, Angelo Avogaro, MD, of the University of Padova, Italy, said that the additional LDL-C lowering effect of alirocumab on top of statins could theoretically halve the projected 10-year risk of cardiovascular disease using data from the two ODYSSEY studies and the UKPDS Risk Engine. Using a baseline 10-year cardiovascular risk of around 26%-28%, this could be reduced to 11%-13%, he suggested.

Of note, Dr. Avogaro said, was that, at baseline, not all patients were on high intensity statins, the majority received moderate doses, with a good number of patients taking none or who were intolerant to statins included. “This, I like,” he observed.

A reassuring point was that there was no signal of having a detrimental effect on neurocognitive dysfunction, Dr. Avogaro observed, which concurs with recent data published on evolocumab (N Engl J Med 2017; 377:633-43).

Nevertheless, longer-follow-up is needed to examine adverse effects, “especially in those insulin-treated patients experiencing severe hypoglycemic reactions.”

The ODYSSEY DM studies were funded by Sanofi and Regeneron Pharmaceuticals.

Dr. Colhoun has received research grants from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Pfizer, Regeneron Pharmaceuticals, Roche Pharmaceuticals, and Sanofi. She has also been a consultant for Eli Lilly, Regeneron Pharmaceuticals, and Sanofi.

Dr. Del Prato has received research funding from AstraZeneca, Boehringer Ingelheim, Novartis, Merck Sharpe & Dohme, and Novo Nordisk. He is a consultant for or has received honoraria from the preceding companies, as well as from Eli Lilly, GlaxoSmithKline, Janssen Pharmaceuticals, Laboratoires Servier, Sanofi-Aventis, and Takeda Pharmaceuticals.

 

LISBON – Additional data released from the ODYSSEY DM clinical trials program show that the PCSK9 inhibitor alirocumab lowers lipid levels works just as well in patients with type 1 diabetes as it does in those with type 2 diabetes, plus it may have an edge over using older, add-on lipid-lowering therapies such as fibrates.

The findings were presented at the annual meeting of the European Association for the Study of Diabetes.

In one study involving 76 insulin-treated patients with T1DM, treatment with alirocumab (Praluent, Sanofi/Regeneron Pharmaceuticals) reduced low-density lipoprotein cholesterol levels by a mean of 47.8% versus placebo from baseline to week 24 (P less than .0001), the primary endpoint of the study.

Furthermore, in a separate study involving 413 patients with T2DM with mixed hyperlipidemia, alirocumab decreased levels of non–high-density lipoprotein cholesterol (non-HDL-C) by 33.3% compared with fenofibrate (P less than .0001).

These new results from the ODYSSEY DM-INSULIN and ODYSSEY DM-DYSLIPIDEMIA trials, respectively, add to those already presented this year at the annual scientific sessions of the American Diabetes Association.

Sara Freeman/Frontline Medical News

At the ADA meeting it was reported that, after 24 weeks, alirocumab therapy cut LDL-C by 49% more than placebo (P less than .0001) in insulin-treated patients with T2DM, and that non-HDL-C fell by 32.5% more compared with usual care (P less than .0001) in the lipid trial.

“We have studied two groups of high- to very-high cardiovascular risk patients with diabetes mellitus: those on insulin and those with mixed dyslipidemia in whom previously only secondary data were available,” said Stefano Del Prato, MD, who presented the lipid study. “These are dedicated studies in these specific populations,” he added.

In these high-risk diabetic populations, Dr. Del Prato, professor of endocrinology and metabolism and chief of the section of diabetes, University of Pisa, Italy, observed “alirocumab was superior in lipid-lowering efficacy compared to standard care, with no specific safety issues.”
 

Efficacy unaffected by co-administration with insulin use

Helen Colhoun, MD, AXA chair of medical informatics and life course epidemiology at the University of Edinburgh, presented the updated findings of the ODYSSEY DM-INSULIN study, which recruited 517 patients, the majority (n = 441) of whom had T2DM.

In the study, alirocumab, a monoclonal antibody that targets proprotein convertase subtilisin–kexin type 9 (PCSK9), was compared with placebo in patients with established atherosclerotic cardiovascular disease or other cardiovascular risk factors, and in whom LDL-C was 70 mg/dL (1.8 mmol/L) or higher.

The percentage change in LDL-C from baseline to week 24 was similarly reduced in T1DM and T2DM, Dr. Colhoun observed, and commensurate with data seen across the ODYSSEY phase III trials program. Of note, the majority of type 2 (80%) and type 1 (63%) patients did not need the dose of alirocumab to be increased and remained on the starting dose of 75 mg every 2 weeks.

Sara Freeman/Frontline Medical News

“It is very pleasing to see no evidence of loss of efficacy of alirocumab among people with type 1 diabetes,” Dr. Colhoun said. Despite the “modest sample size, you can see the treatment effect is highly, clinically, and statistically significant.”

The results of the ODYSSEY DM-INSULIN trial, which were published online, Sept. 14, 2017, to coincide with their presentation at the meeting, also showed that the percentage change in LDL-C over time is “well sustained” and that 70% and 76% of patients with T1DM and T2DM, respectively, can achieve an LDL-C target of less than 70 mg/dL (1.8 mmol/L) and 79% and 71% can hit a non-HDL-C target of less than 100 mg/dL (2.6 mmol/L).

Other lipid parameters – including apolipoprotein (Apo) B, total cholesterol, Lp(a), and triglycerides – were also reduced to a greater extent in patients treated with alirocumab versus those given placebo. Dr. Colhoun drew attention to the reduction in Lp(a), which dropped by 23% in patients with T1DM and by 19% in patients with T2DM, as it is an important risk factor for peripheral vascular disease, and it is not affected by statin therapy.

“What this trial has told us is that coadministering alirocumab with insulin does not adversely affect its efficacy,” said Dr. Colhoun. “There’s absolutely no evidence of alirocumab altering HbA_1c or fasting plasma glucose,” she added. There was also no affect on how patients were treated, either with insulin therapy or antihyperglycemic drugs.

Overall safety findings were “reassuring” and anti-drug antibodies were rare (2.1%) and did not affect the lipid-lowering effects of alirocumab.
 

Alirocumab beats fenofibrate as add-on lipid-lowering therapy

 

Presenting the ODYSSEY DM-DYSLIPIDEMIA data, which involved patients with T2DM, Dr. Del Prato observed that alirocumab was “generally well tolerated” and did not affect HbA_1c or fasting plasma glucose levels.

He presented new data from a prespecified analysis that looked at the subgroup of 72 patients who were randomized into an alirocumab (n = 48) or fenofibrate (n = 24) as usual care arm. Dr. Del Prato reminded the audience that the choice of usual treatment was decided by the study investigators prior to randomizing patients, and that other usual care treatments included in the study were ezetimibe, omega-3 fatty acids, nicotinic acid, or no lipid-lowering therapy.

As in the insulin study, the majority (63.6%) of patients treated with alirocumab remained on the starting dose of 75 mg every 2 weeks and did not need up-titration.

Changes in the percentage of non-HDL-C from baseline over time were greater in the alirocumab group than in the usual care group, both in the overall population and in the fenofibrate subanalysis.

Higher percentages of patients treated with alirocumab achieved non-HDL-C compared with those given usual care (66.9% vs. 17.7% in overall population, 65.2% vs. 10.1% in fenofibrate sub-analysis) and LDL-C (70.8% vs. 16.3% and 71.9% vs. 17.5%, respectively) goals at week 24.

Alirocumab also significantly reduced levels of Apo B, total cholesterol, and Lp(a) versus the overall usual care group and also versus the fenofibrate usual care group, Dr. Del Prato said.

Taking the two studies together, he concluded: “These data support alirocumab as a treatment option in people with diabetes mellitus and hypercholesterolemia despite maximally tolerated statins,” Dr. Del Prato said.
 

Will the lipid-benefits translate into improved cardiovascular outcomes?

The question now is whether the lipid-lowering effects of alirocumab in patients with diabetes will translate into improved cardiovascular outcomes in patients with diabetes.

The results of the ODYSSEY OUTCOMES trial, which is evaluating cardiovascular outcomes during treatment with alirocumab after an acute coronary syndrome, are expected next year. While the trial is not being conducted specifically in patients with diabetes, it is expected that there will be subpopulations of T1DM and T2DM patients included.

Cardiovascular outcomes data on the PCSK9 inhibitor, evolocumab (Repatha, Amgen) in the FOURIER trial were published in March (N Engl J Med 2017;376:1713-22) and provide some evidence that a reduction in major cardiovascular events may be possible with these agents.

Providing independent comment on the study, Angelo Avogaro, MD, of the University of Padova, Italy, said that the additional LDL-C lowering effect of alirocumab on top of statins could theoretically halve the projected 10-year risk of cardiovascular disease using data from the two ODYSSEY studies and the UKPDS Risk Engine. Using a baseline 10-year cardiovascular risk of around 26%-28%, this could be reduced to 11%-13%, he suggested.

Of note, Dr. Avogaro said, was that, at baseline, not all patients were on high intensity statins, the majority received moderate doses, with a good number of patients taking none or who were intolerant to statins included. “This, I like,” he observed.

A reassuring point was that there was no signal of having a detrimental effect on neurocognitive dysfunction, Dr. Avogaro observed, which concurs with recent data published on evolocumab (N Engl J Med 2017; 377:633-43).

Nevertheless, longer-follow-up is needed to examine adverse effects, “especially in those insulin-treated patients experiencing severe hypoglycemic reactions.”

The ODYSSEY DM studies were funded by Sanofi and Regeneron Pharmaceuticals.

Dr. Colhoun has received research grants from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Pfizer, Regeneron Pharmaceuticals, Roche Pharmaceuticals, and Sanofi. She has also been a consultant for Eli Lilly, Regeneron Pharmaceuticals, and Sanofi.

Dr. Del Prato has received research funding from AstraZeneca, Boehringer Ingelheim, Novartis, Merck Sharpe & Dohme, and Novo Nordisk. He is a consultant for or has received honoraria from the preceding companies, as well as from Eli Lilly, GlaxoSmithKline, Janssen Pharmaceuticals, Laboratoires Servier, Sanofi-Aventis, and Takeda Pharmaceuticals.

 

LISBON – Additional data released from the ODYSSEY DM clinical trials program show that the PCSK9 inhibitor alirocumab lowers lipid levels works just as well in patients with type 1 diabetes as it does in those with type 2 diabetes, plus it may have an edge over using older, add-on lipid-lowering therapies such as fibrates.

The findings were presented at the annual meeting of the European Association for the Study of Diabetes.

In one study involving 76 insulin-treated patients with T1DM, treatment with alirocumab (Praluent, Sanofi/Regeneron Pharmaceuticals) reduced low-density lipoprotein cholesterol levels by a mean of 47.8% versus placebo from baseline to week 24 (P less than .0001), the primary endpoint of the study.

Furthermore, in a separate study involving 413 patients with T2DM with mixed hyperlipidemia, alirocumab decreased levels of non–high-density lipoprotein cholesterol (non-HDL-C) by 33.3% compared with fenofibrate (P less than .0001).

These new results from the ODYSSEY DM-INSULIN and ODYSSEY DM-DYSLIPIDEMIA trials, respectively, add to those already presented this year at the annual scientific sessions of the American Diabetes Association.

Sara Freeman/Frontline Medical News

At the ADA meeting it was reported that, after 24 weeks, alirocumab therapy cut LDL-C by 49% more than placebo (P less than .0001) in insulin-treated patients with T2DM, and that non-HDL-C fell by 32.5% more compared with usual care (P less than .0001) in the lipid trial.

“We have studied two groups of high- to very-high cardiovascular risk patients with diabetes mellitus: those on insulin and those with mixed dyslipidemia in whom previously only secondary data were available,” said Stefano Del Prato, MD, who presented the lipid study. “These are dedicated studies in these specific populations,” he added.

In these high-risk diabetic populations, Dr. Del Prato, professor of endocrinology and metabolism and chief of the section of diabetes, University of Pisa, Italy, observed “alirocumab was superior in lipid-lowering efficacy compared to standard care, with no specific safety issues.”
 

Efficacy unaffected by co-administration with insulin use

Helen Colhoun, MD, AXA chair of medical informatics and life course epidemiology at the University of Edinburgh, presented the updated findings of the ODYSSEY DM-INSULIN study, which recruited 517 patients, the majority (n = 441) of whom had T2DM.

In the study, alirocumab, a monoclonal antibody that targets proprotein convertase subtilisin–kexin type 9 (PCSK9), was compared with placebo in patients with established atherosclerotic cardiovascular disease or other cardiovascular risk factors, and in whom LDL-C was 70 mg/dL (1.8 mmol/L) or higher.

The percentage change in LDL-C from baseline to week 24 was similarly reduced in T1DM and T2DM, Dr. Colhoun observed, and commensurate with data seen across the ODYSSEY phase III trials program. Of note, the majority of type 2 (80%) and type 1 (63%) patients did not need the dose of alirocumab to be increased and remained on the starting dose of 75 mg every 2 weeks.

Sara Freeman/Frontline Medical News

“It is very pleasing to see no evidence of loss of efficacy of alirocumab among people with type 1 diabetes,” Dr. Colhoun said. Despite the “modest sample size, you can see the treatment effect is highly, clinically, and statistically significant.”

The results of the ODYSSEY DM-INSULIN trial, which were published online, Sept. 14, 2017, to coincide with their presentation at the meeting, also showed that the percentage change in LDL-C over time is “well sustained” and that 70% and 76% of patients with T1DM and T2DM, respectively, can achieve an LDL-C target of less than 70 mg/dL (1.8 mmol/L) and 79% and 71% can hit a non-HDL-C target of less than 100 mg/dL (2.6 mmol/L).

Other lipid parameters – including apolipoprotein (Apo) B, total cholesterol, Lp(a), and triglycerides – were also reduced to a greater extent in patients treated with alirocumab versus those given placebo. Dr. Colhoun drew attention to the reduction in Lp(a), which dropped by 23% in patients with T1DM and by 19% in patients with T2DM, as it is an important risk factor for peripheral vascular disease, and it is not affected by statin therapy.

“What this trial has told us is that coadministering alirocumab with insulin does not adversely affect its efficacy,” said Dr. Colhoun. “There’s absolutely no evidence of alirocumab altering HbA_1c or fasting plasma glucose,” she added. There was also no affect on how patients were treated, either with insulin therapy or antihyperglycemic drugs.

Overall safety findings were “reassuring” and anti-drug antibodies were rare (2.1%) and did not affect the lipid-lowering effects of alirocumab.
 

Alirocumab beats fenofibrate as add-on lipid-lowering therapy

 

Presenting the ODYSSEY DM-DYSLIPIDEMIA data, which involved patients with T2DM, Dr. Del Prato observed that alirocumab was “generally well tolerated” and did not affect HbA_1c or fasting plasma glucose levels.

He presented new data from a prespecified analysis that looked at the subgroup of 72 patients who were randomized into an alirocumab (n = 48) or fenofibrate (n = 24) as usual care arm. Dr. Del Prato reminded the audience that the choice of usual treatment was decided by the study investigators prior to randomizing patients, and that other usual care treatments included in the study were ezetimibe, omega-3 fatty acids, nicotinic acid, or no lipid-lowering therapy.

As in the insulin study, the majority (63.6%) of patients treated with alirocumab remained on the starting dose of 75 mg every 2 weeks and did not need up-titration.

Changes in the percentage of non-HDL-C from baseline over time were greater in the alirocumab group than in the usual care group, both in the overall population and in the fenofibrate subanalysis.

Higher percentages of patients treated with alirocumab achieved non-HDL-C compared with those given usual care (66.9% vs. 17.7% in overall population, 65.2% vs. 10.1% in fenofibrate sub-analysis) and LDL-C (70.8% vs. 16.3% and 71.9% vs. 17.5%, respectively) goals at week 24.

Alirocumab also significantly reduced levels of Apo B, total cholesterol, and Lp(a) versus the overall usual care group and also versus the fenofibrate usual care group, Dr. Del Prato said.

Taking the two studies together, he concluded: “These data support alirocumab as a treatment option in people with diabetes mellitus and hypercholesterolemia despite maximally tolerated statins,” Dr. Del Prato said.
 

Will the lipid-benefits translate into improved cardiovascular outcomes?

The question now is whether the lipid-lowering effects of alirocumab in patients with diabetes will translate into improved cardiovascular outcomes in patients with diabetes.

The results of the ODYSSEY OUTCOMES trial, which is evaluating cardiovascular outcomes during treatment with alirocumab after an acute coronary syndrome, are expected next year. While the trial is not being conducted specifically in patients with diabetes, it is expected that there will be subpopulations of T1DM and T2DM patients included.

Cardiovascular outcomes data on the PCSK9 inhibitor, evolocumab (Repatha, Amgen) in the FOURIER trial were published in March (N Engl J Med 2017;376:1713-22) and provide some evidence that a reduction in major cardiovascular events may be possible with these agents.

Providing independent comment on the study, Angelo Avogaro, MD, of the University of Padova, Italy, said that the additional LDL-C lowering effect of alirocumab on top of statins could theoretically halve the projected 10-year risk of cardiovascular disease using data from the two ODYSSEY studies and the UKPDS Risk Engine. Using a baseline 10-year cardiovascular risk of around 26%-28%, this could be reduced to 11%-13%, he suggested.

Of note, Dr. Avogaro said, was that, at baseline, not all patients were on high intensity statins, the majority received moderate doses, with a good number of patients taking none or who were intolerant to statins included. “This, I like,” he observed.

A reassuring point was that there was no signal of having a detrimental effect on neurocognitive dysfunction, Dr. Avogaro observed, which concurs with recent data published on evolocumab (N Engl J Med 2017; 377:633-43).

Nevertheless, longer-follow-up is needed to examine adverse effects, “especially in those insulin-treated patients experiencing severe hypoglycemic reactions.”

The ODYSSEY DM studies were funded by Sanofi and Regeneron Pharmaceuticals.

Dr. Colhoun has received research grants from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Pfizer, Regeneron Pharmaceuticals, Roche Pharmaceuticals, and Sanofi. She has also been a consultant for Eli Lilly, Regeneron Pharmaceuticals, and Sanofi.

Dr. Del Prato has received research funding from AstraZeneca, Boehringer Ingelheim, Novartis, Merck Sharpe & Dohme, and Novo Nordisk. He is a consultant for or has received honoraria from the preceding companies, as well as from Eli Lilly, GlaxoSmithKline, Janssen Pharmaceuticals, Laboratoires Servier, Sanofi-Aventis, and Takeda Pharmaceuticals.

 

Patients with type 2 diabetes who took once-daily exenatide did not appear to have an increase in their overall cardiovascular risk, compared with those who took placebo, a large randomized trial demonstrated.

“We did not observe any specific safety issues during our trial; there was no adverse signal with respect to heart failure, despite the higher mean heart rate in the exenatide group than in the placebo group, and events of acute pancreatitis and pancreatic cancer were rare, with similar rates in the two groups,” according to researchers led by Rury R. Holman, F.Med.Sci. Their study was published online Sept. 14 in the New England Journal of Medicine, and was presented at the annual meeting of the European Association for the Study of Diabetes.

For the trial, which was funded by Amylin Pharmaceuticals and known as the Exenatide Study of Cardiovascular Event Lowering (EXSCEL), the researchers randomly assigned 14,752 patients with type 2 diabetes at 687 sites in 35 countries to receive subcutaneous injections of extended-released exenatide at a dose of 2 mg, or matching placebo once per week, from June 18, 2010, through Sept. 16, 2015. The patients were followed for a median of 3.2 years and the main outcome of interest was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or stroke.

Dr. Holman, professor of diabetic medicine at Oxford (England) University and director of the University of Oxford Diabetes Trials Unit of the Oxford Center for Diabetes, England, and his associates reported that 10,782 of the 14,752 patients (73.1%) had previous cardiovascular disease. A primary composite outcome event occurred in 11.4% of patients in the exenatide group, compared with 12.2% of those in the placebo group, which translated into a hazard ratio of 0.91.

In the meantime, the intention-to-treat analysis revealed that exenatide was noninferior to placebo with respect to safety (P less than .001) but was not superior to placebo with respect to safety (P = .06). The researchers observed no significant differences between the two groups in the rates of death from cardiovascular causes, fatal or nonfatal MI, or stroke, hospitalization for heart failure or for acute coronary syndrome, or in the incidence of cute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events.

“The pragmatic design of the trial included integration with usual care and wide-ranging eligibility criteria,” the researchers wrote. “For example, patients with any degree of cardiovascular risk who were at least 18 years of age (with no upper age limit) were eligible. To further augment the potential generalizability of any findings, we evaluated the cardiovascular effect of once-weekly extended-release exenatide in the usual-care setting by maintaining the focus of management of diabetes and cardiovascular risk with the usual-care provider.”

The researchers acknowledged certain limitations of the study, including the rate of premature discontinuation of the trial regimen, “which was driven by patient decision. We speculate that probable factors for discontinuation were the complexity of the first-generation injection device that was used and the fact that our trial had no run-in period.”

The trial was conducted jointly by the Duke Clinical Research Institute and the University of Oxford Diabetes Trial Unit, in collaboration with Amylin Pharmaceuticals. Dr. Holman and his coauthors reported having numerous financial ties to the pharmaceutical industry.

[email protected]

PRIMARY SOURCE: N Engl J Med 2017 Sept. 14. doi: 10.1056/NEJMoa1612917

 

Patients with type 2 diabetes who took once-daily exenatide did not appear to have an increase in their overall cardiovascular risk, compared with those who took placebo, a large randomized trial demonstrated.

“We did not observe any specific safety issues during our trial; there was no adverse signal with respect to heart failure, despite the higher mean heart rate in the exenatide group than in the placebo group, and events of acute pancreatitis and pancreatic cancer were rare, with similar rates in the two groups,” according to researchers led by Rury R. Holman, F.Med.Sci. Their study was published online Sept. 14 in the New England Journal of Medicine, and was presented at the annual meeting of the European Association for the Study of Diabetes.

For the trial, which was funded by Amylin Pharmaceuticals and known as the Exenatide Study of Cardiovascular Event Lowering (EXSCEL), the researchers randomly assigned 14,752 patients with type 2 diabetes at 687 sites in 35 countries to receive subcutaneous injections of extended-released exenatide at a dose of 2 mg, or matching placebo once per week, from June 18, 2010, through Sept. 16, 2015. The patients were followed for a median of 3.2 years and the main outcome of interest was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or stroke.

Dr. Holman, professor of diabetic medicine at Oxford (England) University and director of the University of Oxford Diabetes Trials Unit of the Oxford Center for Diabetes, England, and his associates reported that 10,782 of the 14,752 patients (73.1%) had previous cardiovascular disease. A primary composite outcome event occurred in 11.4% of patients in the exenatide group, compared with 12.2% of those in the placebo group, which translated into a hazard ratio of 0.91.

In the meantime, the intention-to-treat analysis revealed that exenatide was noninferior to placebo with respect to safety (P less than .001) but was not superior to placebo with respect to safety (P = .06). The researchers observed no significant differences between the two groups in the rates of death from cardiovascular causes, fatal or nonfatal MI, or stroke, hospitalization for heart failure or for acute coronary syndrome, or in the incidence of cute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events.

“The pragmatic design of the trial included integration with usual care and wide-ranging eligibility criteria,” the researchers wrote. “For example, patients with any degree of cardiovascular risk who were at least 18 years of age (with no upper age limit) were eligible. To further augment the potential generalizability of any findings, we evaluated the cardiovascular effect of once-weekly extended-release exenatide in the usual-care setting by maintaining the focus of management of diabetes and cardiovascular risk with the usual-care provider.”

The researchers acknowledged certain limitations of the study, including the rate of premature discontinuation of the trial regimen, “which was driven by patient decision. We speculate that probable factors for discontinuation were the complexity of the first-generation injection device that was used and the fact that our trial had no run-in period.”

The trial was conducted jointly by the Duke Clinical Research Institute and the University of Oxford Diabetes Trial Unit, in collaboration with Amylin Pharmaceuticals. Dr. Holman and his coauthors reported having numerous financial ties to the pharmaceutical industry.

[email protected]

PRIMARY SOURCE: N Engl J Med 2017 Sept. 14. doi: 10.1056/NEJMoa1612917

 

Patients with type 2 diabetes who took once-daily exenatide did not appear to have an increase in their overall cardiovascular risk, compared with those who took placebo, a large randomized trial demonstrated.

“We did not observe any specific safety issues during our trial; there was no adverse signal with respect to heart failure, despite the higher mean heart rate in the exenatide group than in the placebo group, and events of acute pancreatitis and pancreatic cancer were rare, with similar rates in the two groups,” according to researchers led by Rury R. Holman, F.Med.Sci. Their study was published online Sept. 14 in the New England Journal of Medicine, and was presented at the annual meeting of the European Association for the Study of Diabetes.

For the trial, which was funded by Amylin Pharmaceuticals and known as the Exenatide Study of Cardiovascular Event Lowering (EXSCEL), the researchers randomly assigned 14,752 patients with type 2 diabetes at 687 sites in 35 countries to receive subcutaneous injections of extended-released exenatide at a dose of 2 mg, or matching placebo once per week, from June 18, 2010, through Sept. 16, 2015. The patients were followed for a median of 3.2 years and the main outcome of interest was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or stroke.

Dr. Holman, professor of diabetic medicine at Oxford (England) University and director of the University of Oxford Diabetes Trials Unit of the Oxford Center for Diabetes, England, and his associates reported that 10,782 of the 14,752 patients (73.1%) had previous cardiovascular disease. A primary composite outcome event occurred in 11.4% of patients in the exenatide group, compared with 12.2% of those in the placebo group, which translated into a hazard ratio of 0.91.

In the meantime, the intention-to-treat analysis revealed that exenatide was noninferior to placebo with respect to safety (P less than .001) but was not superior to placebo with respect to safety (P = .06). The researchers observed no significant differences between the two groups in the rates of death from cardiovascular causes, fatal or nonfatal MI, or stroke, hospitalization for heart failure or for acute coronary syndrome, or in the incidence of cute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events.

“The pragmatic design of the trial included integration with usual care and wide-ranging eligibility criteria,” the researchers wrote. “For example, patients with any degree of cardiovascular risk who were at least 18 years of age (with no upper age limit) were eligible. To further augment the potential generalizability of any findings, we evaluated the cardiovascular effect of once-weekly extended-release exenatide in the usual-care setting by maintaining the focus of management of diabetes and cardiovascular risk with the usual-care provider.”

The researchers acknowledged certain limitations of the study, including the rate of premature discontinuation of the trial regimen, “which was driven by patient decision. We speculate that probable factors for discontinuation were the complexity of the first-generation injection device that was used and the fact that our trial had no run-in period.”

The trial was conducted jointly by the Duke Clinical Research Institute and the University of Oxford Diabetes Trial Unit, in collaboration with Amylin Pharmaceuticals. Dr. Holman and his coauthors reported having numerous financial ties to the pharmaceutical industry.

[email protected]

PRIMARY SOURCE: N Engl J Med 2017 Sept. 14. doi: 10.1056/NEJMoa1612917

 

LISBON – Patients with type 2 diabetes mellitus who also have moderate-to-severe chronic kidney disease (CKD) may be as effectively treated with the glucagonlike peptide–1 receptor agonist dulaglutide (Trulicity) as insulin glargine, the results of an international study showed.

Although comparable effects on glycemic control were seen, patients who received dulaglutide rather than insulin glargine in conjunction with prandial insulin lispro (Humalog) exhibited greater weight loss, had fewer episodes of hypoglycemia, and experienced beneficial effects on two important renal parameters.

Sara Freeman/Frontline Medical News

There was “greater albuminuria reduction and markedly reduced eGFR [estimated glomerular filtration rate] decline” with dulaglutide than with insulin glargine, Katherine Tuttle, MD, reported at the annual meeting of the European Association for the Study of Diabetes.

The adverse event profile of dulaglutide was typical of that seen with GLP-1 receptor antagonism, noted Dr. Tuttle, who is the executive director of Providence Medical Research Center, Providence Sacred Heart Medical Center in Spokane, Washington, and clinical professor of medicine in the nephrology division at the University of Washington in Seattle.

In Europe, the use of dulaglutide in patients with severely reduced kidney function is not currently recommended, and monitoring is required in the United States in those with gastrointestinal side effects.

AWARD-7 was a randomized, open-label parallel-arm study comparing once-weekly dulaglutide (0.75 mg or 1.5 mg) with insulin glargine plus prandial insulin lispro in 576 subjects who had T2DM and stage 3-4 chronic kidney disease. The aim of the trial was to show noninferiority of the dulaglutide regimen to the insulin glargine regimen.

The trial was open label because the dose of insulin glargine had to be regulated, Dr. Tuttle explained, but the dose of dulaglutide given was blinded. The dose of insulin glargine was targeted to fasting plasma glucose to achieve a value between 5.6 mmol/L and 8.3 mmol/L. The dose of insulin lispro was also adjusted to target preprandial plasma glucose between 6.7 mmol/L and 10.0 mmol/L.

Patients were included if they had a glycated hemoglobin (HbA_1c) level of at least 7.5% but less than or equal to 10.5% (at least 57 but less than or equal to 91 mmol/mol) and an eGFR less than 60 but greater than or equal to 15 mL/min per 1.73 m² at screening.

Approximately 45% of dulaglutide- and 52% of glargine-treated subjects were women; the average age of participants was 65 years, with an average duration of diabetes of around 18 years. The mean HbA_1c level at study entry was 8.6% (70.5 mmol/mol), with around half of participants having a HbA_1c above 8.5% (69.4 mmol/mol) at entry.

The majority of patients included had an eGFR of less than 45 mL/min per 1.73 m², and about 30% of patients had stage 4 CKD (eGFR at least 15 but less than 30 mL/min per 1.73 m²), about 45% had macroalbuminuria, and a third or more had microalbuminuria.

The primary endpoint was change in HbA_1c from baseline to week 26, and this was comparable for both dulaglutide (at around –1.1% to –1.2%) and insulin glargine (around –1.1%). The effects were maintained at 52 weeks, Dr. Tuttle said, adding that similar percentages (approximately 70% or more) of patients in the groups achieved a target HbA_1c of less than 8.0 (64 mmol/mol) at 26 and at 52 weeks. Similar results were seen when the more conventional target of less than 7% (less than 52 mmol/mol) was used, with around 30% of patients achieving this target at 26 and at 52 weeks.

As for weight change, the insulin-treated patients gained about 1 kg in weight over the full course of the study while a dose-dependent decrease in weight of about 2-3 kg was seen with dulaglutide treatment.

“Rates of hypoglycemia were consistently lower in the dulaglutide groups [than in the glargine group],” Dr. Tuttle said, noting “the lowest rates of hypoglycemia were actually seen with the highest dose of dulaglutide.”

The rate of total hypoglycemia (less than or equal to 3.9 mmol/mol) in the 1.5-mg and 0.75-mg dulaglutide groups was 50% and 59.8% of patients, respectively, versus almost 75% of the glargine-treated patients. Rates for documented symptomatic (40.5%, 48.1%, 63.4%), nocturnal (20.5%, 23.8%, 47.9%), and severe (0%, 2.6%, 6.7%) hypoglycemia followed a similar pattern.

“Albuminuria was reduced in all study groups, but there were greater reductions in the patients receiving dulaglutide at 26 weeks,” Dr. Tuttle said. The mean change in UACR from baseline to week 26 was –27.7 for the 1.5-mg dose of dulaglutide, –26.7 for the 0.75-mg dose, and –16.4 for insulin glargine.

The expected rate of eGFR decline at week 26 was also lower with dulaglutide 1.5 mg and 0.75 mg than with glargine, at a respective –0.8%, –3.3%, and –7.7% or –0.1, –0.4, and –1.9 mL/min per 1.73 m².

“In patients at this stage of CKD, we expect about a 4- to 5-mL per minute loss, so they are right on target or as expected in the insulin group, but this was essentially extinguished in the dulaglutide groups, where there was no significant loss in eGFR during the 26-week time period,” said Dr. Tuttle.

The only difference in side effect profiles between the dulaglutide groups and the glargine group was a higher rate of gastrointestinal side effects. Nausea was seen in 19.8%, 14.2%, and 4.6% of patients given the dulaglutide 1.5 mg, dulaglutide 0.75 mg, and glargine, respectively, with vomiting reported by 13.5%, 8.4%, and 4.6%.

Eli Lilly funded the study. Dr. Tuttle disclosed acting as a consultant on therapies for diabetic kidney disease for Eli Lilly, Boehringer Ingelheim, Gilead, and AstraZeneca.

This article was updated September 28, 2017.

 

LISBON – Patients with type 2 diabetes mellitus who also have moderate-to-severe chronic kidney disease (CKD) may be as effectively treated with the glucagonlike peptide–1 receptor agonist dulaglutide (Trulicity) as insulin glargine, the results of an international study showed.

Although comparable effects on glycemic control were seen, patients who received dulaglutide rather than insulin glargine in conjunction with prandial insulin lispro (Humalog) exhibited greater weight loss, had fewer episodes of hypoglycemia, and experienced beneficial effects on two important renal parameters.

Sara Freeman/Frontline Medical News

There was “greater albuminuria reduction and markedly reduced eGFR [estimated glomerular filtration rate] decline” with dulaglutide than with insulin glargine, Katherine Tuttle, MD, reported at the annual meeting of the European Association for the Study of Diabetes.

The adverse event profile of dulaglutide was typical of that seen with GLP-1 receptor antagonism, noted Dr. Tuttle, who is the executive director of Providence Medical Research Center, Providence Sacred Heart Medical Center in Spokane, Washington, and clinical professor of medicine in the nephrology division at the University of Washington in Seattle.

In Europe, the use of dulaglutide in patients with severely reduced kidney function is not currently recommended, and monitoring is required in the United States in those with gastrointestinal side effects.

AWARD-7 was a randomized, open-label parallel-arm study comparing once-weekly dulaglutide (0.75 mg or 1.5 mg) with insulin glargine plus prandial insulin lispro in 576 subjects who had T2DM and stage 3-4 chronic kidney disease. The aim of the trial was to show noninferiority of the dulaglutide regimen to the insulin glargine regimen.

The trial was open label because the dose of insulin glargine had to be regulated, Dr. Tuttle explained, but the dose of dulaglutide given was blinded. The dose of insulin glargine was targeted to fasting plasma glucose to achieve a value between 5.6 mmol/L and 8.3 mmol/L. The dose of insulin lispro was also adjusted to target preprandial plasma glucose between 6.7 mmol/L and 10.0 mmol/L.

Patients were included if they had a glycated hemoglobin (HbA_1c) level of at least 7.5% but less than or equal to 10.5% (at least 57 but less than or equal to 91 mmol/mol) and an eGFR less than 60 but greater than or equal to 15 mL/min per 1.73 m² at screening.

Approximately 45% of dulaglutide- and 52% of glargine-treated subjects were women; the average age of participants was 65 years, with an average duration of diabetes of around 18 years. The mean HbA_1c level at study entry was 8.6% (70.5 mmol/mol), with around half of participants having a HbA_1c above 8.5% (69.4 mmol/mol) at entry.

The majority of patients included had an eGFR of less than 45 mL/min per 1.73 m², and about 30% of patients had stage 4 CKD (eGFR at least 15 but less than 30 mL/min per 1.73 m²), about 45% had macroalbuminuria, and a third or more had microalbuminuria.

The primary endpoint was change in HbA_1c from baseline to week 26, and this was comparable for both dulaglutide (at around –1.1% to –1.2%) and insulin glargine (around –1.1%). The effects were maintained at 52 weeks, Dr. Tuttle said, adding that similar percentages (approximately 70% or more) of patients in the groups achieved a target HbA_1c of less than 8.0 (64 mmol/mol) at 26 and at 52 weeks. Similar results were seen when the more conventional target of less than 7% (less than 52 mmol/mol) was used, with around 30% of patients achieving this target at 26 and at 52 weeks.

As for weight change, the insulin-treated patients gained about 1 kg in weight over the full course of the study while a dose-dependent decrease in weight of about 2-3 kg was seen with dulaglutide treatment.

“Rates of hypoglycemia were consistently lower in the dulaglutide groups [than in the glargine group],” Dr. Tuttle said, noting “the lowest rates of hypoglycemia were actually seen with the highest dose of dulaglutide.”

The rate of total hypoglycemia (less than or equal to 3.9 mmol/mol) in the 1.5-mg and 0.75-mg dulaglutide groups was 50% and 59.8% of patients, respectively, versus almost 75% of the glargine-treated patients. Rates for documented symptomatic (40.5%, 48.1%, 63.4%), nocturnal (20.5%, 23.8%, 47.9%), and severe (0%, 2.6%, 6.7%) hypoglycemia followed a similar pattern.

“Albuminuria was reduced in all study groups, but there were greater reductions in the patients receiving dulaglutide at 26 weeks,” Dr. Tuttle said. The mean change in UACR from baseline to week 26 was –27.7 for the 1.5-mg dose of dulaglutide, –26.7 for the 0.75-mg dose, and –16.4 for insulin glargine.

The expected rate of eGFR decline at week 26 was also lower with dulaglutide 1.5 mg and 0.75 mg than with glargine, at a respective –0.8%, –3.3%, and –7.7% or –0.1, –0.4, and –1.9 mL/min per 1.73 m².

“In patients at this stage of CKD, we expect about a 4- to 5-mL per minute loss, so they are right on target or as expected in the insulin group, but this was essentially extinguished in the dulaglutide groups, where there was no significant loss in eGFR during the 26-week time period,” said Dr. Tuttle.

The only difference in side effect profiles between the dulaglutide groups and the glargine group was a higher rate of gastrointestinal side effects. Nausea was seen in 19.8%, 14.2%, and 4.6% of patients given the dulaglutide 1.5 mg, dulaglutide 0.75 mg, and glargine, respectively, with vomiting reported by 13.5%, 8.4%, and 4.6%.

Eli Lilly funded the study. Dr. Tuttle disclosed acting as a consultant on therapies for diabetic kidney disease for Eli Lilly, Boehringer Ingelheim, Gilead, and AstraZeneca.

This article was updated September 28, 2017.

 

LISBON – Patients with type 2 diabetes mellitus who also have moderate-to-severe chronic kidney disease (CKD) may be as effectively treated with the glucagonlike peptide–1 receptor agonist dulaglutide (Trulicity) as insulin glargine, the results of an international study showed.

Although comparable effects on glycemic control were seen, patients who received dulaglutide rather than insulin glargine in conjunction with prandial insulin lispro (Humalog) exhibited greater weight loss, had fewer episodes of hypoglycemia, and experienced beneficial effects on two important renal parameters.

Sara Freeman/Frontline Medical News

There was “greater albuminuria reduction and markedly reduced eGFR [estimated glomerular filtration rate] decline” with dulaglutide than with insulin glargine, Katherine Tuttle, MD, reported at the annual meeting of the European Association for the Study of Diabetes.

The adverse event profile of dulaglutide was typical of that seen with GLP-1 receptor antagonism, noted Dr. Tuttle, who is the executive director of Providence Medical Research Center, Providence Sacred Heart Medical Center in Spokane, Washington, and clinical professor of medicine in the nephrology division at the University of Washington in Seattle.

In Europe, the use of dulaglutide in patients with severely reduced kidney function is not currently recommended, and monitoring is required in the United States in those with gastrointestinal side effects.

AWARD-7 was a randomized, open-label parallel-arm study comparing once-weekly dulaglutide (0.75 mg or 1.5 mg) with insulin glargine plus prandial insulin lispro in 576 subjects who had T2DM and stage 3-4 chronic kidney disease. The aim of the trial was to show noninferiority of the dulaglutide regimen to the insulin glargine regimen.

The trial was open label because the dose of insulin glargine had to be regulated, Dr. Tuttle explained, but the dose of dulaglutide given was blinded. The dose of insulin glargine was targeted to fasting plasma glucose to achieve a value between 5.6 mmol/L and 8.3 mmol/L. The dose of insulin lispro was also adjusted to target preprandial plasma glucose between 6.7 mmol/L and 10.0 mmol/L.

Patients were included if they had a glycated hemoglobin (HbA_1c) level of at least 7.5% but less than or equal to 10.5% (at least 57 but less than or equal to 91 mmol/mol) and an eGFR less than 60 but greater than or equal to 15 mL/min per 1.73 m² at screening.

Approximately 45% of dulaglutide- and 52% of glargine-treated subjects were women; the average age of participants was 65 years, with an average duration of diabetes of around 18 years. The mean HbA_1c level at study entry was 8.6% (70.5 mmol/mol), with around half of participants having a HbA_1c above 8.5% (69.4 mmol/mol) at entry.

The majority of patients included had an eGFR of less than 45 mL/min per 1.73 m², and about 30% of patients had stage 4 CKD (eGFR at least 15 but less than 30 mL/min per 1.73 m²), about 45% had macroalbuminuria, and a third or more had microalbuminuria.

The primary endpoint was change in HbA_1c from baseline to week 26, and this was comparable for both dulaglutide (at around –1.1% to –1.2%) and insulin glargine (around –1.1%). The effects were maintained at 52 weeks, Dr. Tuttle said, adding that similar percentages (approximately 70% or more) of patients in the groups achieved a target HbA_1c of less than 8.0 (64 mmol/mol) at 26 and at 52 weeks. Similar results were seen when the more conventional target of less than 7% (less than 52 mmol/mol) was used, with around 30% of patients achieving this target at 26 and at 52 weeks.

As for weight change, the insulin-treated patients gained about 1 kg in weight over the full course of the study while a dose-dependent decrease in weight of about 2-3 kg was seen with dulaglutide treatment.

“Rates of hypoglycemia were consistently lower in the dulaglutide groups [than in the glargine group],” Dr. Tuttle said, noting “the lowest rates of hypoglycemia were actually seen with the highest dose of dulaglutide.”

The rate of total hypoglycemia (less than or equal to 3.9 mmol/mol) in the 1.5-mg and 0.75-mg dulaglutide groups was 50% and 59.8% of patients, respectively, versus almost 75% of the glargine-treated patients. Rates for documented symptomatic (40.5%, 48.1%, 63.4%), nocturnal (20.5%, 23.8%, 47.9%), and severe (0%, 2.6%, 6.7%) hypoglycemia followed a similar pattern.

“Albuminuria was reduced in all study groups, but there were greater reductions in the patients receiving dulaglutide at 26 weeks,” Dr. Tuttle said. The mean change in UACR from baseline to week 26 was –27.7 for the 1.5-mg dose of dulaglutide, –26.7 for the 0.75-mg dose, and –16.4 for insulin glargine.

The expected rate of eGFR decline at week 26 was also lower with dulaglutide 1.5 mg and 0.75 mg than with glargine, at a respective –0.8%, –3.3%, and –7.7% or –0.1, –0.4, and –1.9 mL/min per 1.73 m².

“In patients at this stage of CKD, we expect about a 4- to 5-mL per minute loss, so they are right on target or as expected in the insulin group, but this was essentially extinguished in the dulaglutide groups, where there was no significant loss in eGFR during the 26-week time period,” said Dr. Tuttle.

The only difference in side effect profiles between the dulaglutide groups and the glargine group was a higher rate of gastrointestinal side effects. Nausea was seen in 19.8%, 14.2%, and 4.6% of patients given the dulaglutide 1.5 mg, dulaglutide 0.75 mg, and glargine, respectively, with vomiting reported by 13.5%, 8.4%, and 4.6%.

Eli Lilly funded the study. Dr. Tuttle disclosed acting as a consultant on therapies for diabetic kidney disease for Eli Lilly, Boehringer Ingelheim, Gilead, and AstraZeneca.

This article was updated September 28, 2017.

 

Few patients who are initiated on second-line treatment for type 2 diabetes mellitus show evidence of recommended use of first-line treatment with metformin, according to research published online Sept. 13 in Diabetes Care.

A retrospective cross-sectional study examined Aetna member claims data from 52,544 individuals with type 2 diabetes. It showed that of the 22,956 individuals given second-line treatment, only 8.2% had claims evidence of recommended use of metformin in the previous 60 days.

Furthermore, 28% had no claims evidence at all of having taken metformin, and only a small number of these patients had evidence of contraindications to metformin, such as heart failure (2.9%), chronic obstructive pulmonary disease (3.1%), liver diseases (4.3%), or renal diseases (4.1%).

“Although gastrointestinal adverse effects related to metformin therapy might lead to guideline nonadherence and early second-line medication initiation, we did not find evidence for gastrointestinal upset in the claims data,” wrote Yi-Ju Tseng, PhD, of the Computational Health Informatics Program at Boston Children’s Hospital, and her coauthors.

Even at the top range of sensitivity, researchers argued that less than half of the patients on second-line treatment could have had prior recommended use of metformin as the first-line treatment, while at the lower end of sensitivity, that figure was less than 10% (Diabetes Care. 2017 Sep 13. doi: 10.2337/dc17-0213).

Wavebreakmedia Ltd

Around one-third of patients received some metformin before beginning a second-line treatment, but the duration of metformin treatment was less than the 2 months recommended by current guidelines. Of these patients, just over half were prescribed both metformin and the second-line medication on the same day.

“What may be taken as evidence of treatment failure by clinicians may instead represent failure of adherence to established treatment guidelines, which in turn may lead to the use of insulin or additional second-line medications,” the authors wrote. “Point-of-care decision support and population health–level approaches should focus on improving adherence to first-line therapy.”

The study also found that patients who were given a second-line treatment without evidence of recommended first-line use of metformin were significantly more likely to be given insulin or an additional second-line antihyperglycemic medication. They were also more likely to be male.

However, the authors acknowledged that retrospective claims-based analyses were limited by the exclusion of uninsured patients, and a lack of detailed clinical or behavioral information, or information on out-of-pocket medications.

The study was supported by the National Institute of General Medical Sciences, and one author was supported by grants from the Ministry of Science and Technology, Taiwan and Chang Gung Memorial Hospital, Linkou, Taiwan. No conflicts of interest were declared.

 

 

Few patients who are initiated on second-line treatment for type 2 diabetes mellitus show evidence of recommended use of first-line treatment with metformin, according to research published online Sept. 13 in Diabetes Care.

A retrospective cross-sectional study examined Aetna member claims data from 52,544 individuals with type 2 diabetes. It showed that of the 22,956 individuals given second-line treatment, only 8.2% had claims evidence of recommended use of metformin in the previous 60 days.

Furthermore, 28% had no claims evidence at all of having taken metformin, and only a small number of these patients had evidence of contraindications to metformin, such as heart failure (2.9%), chronic obstructive pulmonary disease (3.1%), liver diseases (4.3%), or renal diseases (4.1%).

“Although gastrointestinal adverse effects related to metformin therapy might lead to guideline nonadherence and early second-line medication initiation, we did not find evidence for gastrointestinal upset in the claims data,” wrote Yi-Ju Tseng, PhD, of the Computational Health Informatics Program at Boston Children’s Hospital, and her coauthors.

Even at the top range of sensitivity, researchers argued that less than half of the patients on second-line treatment could have had prior recommended use of metformin as the first-line treatment, while at the lower end of sensitivity, that figure was less than 10% (Diabetes Care. 2017 Sep 13. doi: 10.2337/dc17-0213).

Wavebreakmedia Ltd

Around one-third of patients received some metformin before beginning a second-line treatment, but the duration of metformin treatment was less than the 2 months recommended by current guidelines. Of these patients, just over half were prescribed both metformin and the second-line medication on the same day.

“What may be taken as evidence of treatment failure by clinicians may instead represent failure of adherence to established treatment guidelines, which in turn may lead to the use of insulin or additional second-line medications,” the authors wrote. “Point-of-care decision support and population health–level approaches should focus on improving adherence to first-line therapy.”

The study also found that patients who were given a second-line treatment without evidence of recommended first-line use of metformin were significantly more likely to be given insulin or an additional second-line antihyperglycemic medication. They were also more likely to be male.

However, the authors acknowledged that retrospective claims-based analyses were limited by the exclusion of uninsured patients, and a lack of detailed clinical or behavioral information, or information on out-of-pocket medications.

The study was supported by the National Institute of General Medical Sciences, and one author was supported by grants from the Ministry of Science and Technology, Taiwan and Chang Gung Memorial Hospital, Linkou, Taiwan. No conflicts of interest were declared.

 

 

Few patients who are initiated on second-line treatment for type 2 diabetes mellitus show evidence of recommended use of first-line treatment with metformin, according to research published online Sept. 13 in Diabetes Care.

A retrospective cross-sectional study examined Aetna member claims data from 52,544 individuals with type 2 diabetes. It showed that of the 22,956 individuals given second-line treatment, only 8.2% had claims evidence of recommended use of metformin in the previous 60 days.

Furthermore, 28% had no claims evidence at all of having taken metformin, and only a small number of these patients had evidence of contraindications to metformin, such as heart failure (2.9%), chronic obstructive pulmonary disease (3.1%), liver diseases (4.3%), or renal diseases (4.1%).

“Although gastrointestinal adverse effects related to metformin therapy might lead to guideline nonadherence and early second-line medication initiation, we did not find evidence for gastrointestinal upset in the claims data,” wrote Yi-Ju Tseng, PhD, of the Computational Health Informatics Program at Boston Children’s Hospital, and her coauthors.

Even at the top range of sensitivity, researchers argued that less than half of the patients on second-line treatment could have had prior recommended use of metformin as the first-line treatment, while at the lower end of sensitivity, that figure was less than 10% (Diabetes Care. 2017 Sep 13. doi: 10.2337/dc17-0213).

Wavebreakmedia Ltd

Around one-third of patients received some metformin before beginning a second-line treatment, but the duration of metformin treatment was less than the 2 months recommended by current guidelines. Of these patients, just over half were prescribed both metformin and the second-line medication on the same day.

“What may be taken as evidence of treatment failure by clinicians may instead represent failure of adherence to established treatment guidelines, which in turn may lead to the use of insulin or additional second-line medications,” the authors wrote. “Point-of-care decision support and population health–level approaches should focus on improving adherence to first-line therapy.”

The study also found that patients who were given a second-line treatment without evidence of recommended first-line use of metformin were significantly more likely to be given insulin or an additional second-line antihyperglycemic medication. They were also more likely to be male.

However, the authors acknowledged that retrospective claims-based analyses were limited by the exclusion of uninsured patients, and a lack of detailed clinical or behavioral information, or information on out-of-pocket medications.

The study was supported by the National Institute of General Medical Sciences, and one author was supported by grants from the Ministry of Science and Technology, Taiwan and Chang Gung Memorial Hospital, Linkou, Taiwan. No conflicts of interest were declared.