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Fast-acting, mealtime insulin aspart is approved for kids
making it the first fast-acting mealtime insulin injection that does not come with a premeal dosing recommendation, according to a release.
The injection is now available in various dosing options for both adult and pediatric patients with diabetes. Fast-acting mealtime insulin was approved in September 2017 for adults with type 1 or 2 disease, and in October 2019, it was approved for use in insulin pumps for adults.
The most recent approval was based on findings from the onset 7 trial, a 26-week, phase 3b, partially double-blind, treat-to-target trial that included 777 patients aged 1-18 years and demonstrated noninferiority to ordinary, non–fast-acting insulin aspart (Diabetes Care. 2019 Jul;42[7]:1255-62).
Removal of the premeal dosing requirement could help better manage mealtime insulin needs in children, according to the release from Novo Nordisk.
Use of the mealtime insulin injection comes with concerns of serious side effects, such as hypoglycemia, hypokalemia, serious allergic reactions, and heart failure. Common side effects can include skin problems (such as rash, itching, and swelling), injection-site reactions, and weight gain.
making it the first fast-acting mealtime insulin injection that does not come with a premeal dosing recommendation, according to a release.
The injection is now available in various dosing options for both adult and pediatric patients with diabetes. Fast-acting mealtime insulin was approved in September 2017 for adults with type 1 or 2 disease, and in October 2019, it was approved for use in insulin pumps for adults.
The most recent approval was based on findings from the onset 7 trial, a 26-week, phase 3b, partially double-blind, treat-to-target trial that included 777 patients aged 1-18 years and demonstrated noninferiority to ordinary, non–fast-acting insulin aspart (Diabetes Care. 2019 Jul;42[7]:1255-62).
Removal of the premeal dosing requirement could help better manage mealtime insulin needs in children, according to the release from Novo Nordisk.
Use of the mealtime insulin injection comes with concerns of serious side effects, such as hypoglycemia, hypokalemia, serious allergic reactions, and heart failure. Common side effects can include skin problems (such as rash, itching, and swelling), injection-site reactions, and weight gain.
making it the first fast-acting mealtime insulin injection that does not come with a premeal dosing recommendation, according to a release.
The injection is now available in various dosing options for both adult and pediatric patients with diabetes. Fast-acting mealtime insulin was approved in September 2017 for adults with type 1 or 2 disease, and in October 2019, it was approved for use in insulin pumps for adults.
The most recent approval was based on findings from the onset 7 trial, a 26-week, phase 3b, partially double-blind, treat-to-target trial that included 777 patients aged 1-18 years and demonstrated noninferiority to ordinary, non–fast-acting insulin aspart (Diabetes Care. 2019 Jul;42[7]:1255-62).
Removal of the premeal dosing requirement could help better manage mealtime insulin needs in children, according to the release from Novo Nordisk.
Use of the mealtime insulin injection comes with concerns of serious side effects, such as hypoglycemia, hypokalemia, serious allergic reactions, and heart failure. Common side effects can include skin problems (such as rash, itching, and swelling), injection-site reactions, and weight gain.
Farxiga granted Priority Review for treatment of adults with HFrEF
The Food and Drug Administration has accepted a supplemental New Drug Application and granted Priority Review for dapagliflozin (Farxiga) for the reduction of risk of cardiovascular death or worsening of heart failure in adult patients with heart failure with reduced ejection fraction (HFrEF).
The application was based on results from the landmark, phase 3 DAPA-HF trial, published in September 2019 in the New England Journal of Medicine. The study showed that dapagliflozin plus standard care reduced the incidence of cardiovascular death and worsening of heart failure versus placebo in patients with HFrEF.
Dapagliflozin was granted Fast Track designation for heart failure by the FDA in September 2019. In August 2019, the FDA also granted Fast Track designation to dapagliflozin for the delayed progression of renal failure and prevention of cardiovascular and renal death in patients with chronic kidney disease.
The drug is currently indicated for the improvement of glycemic control in adults with type 2 diabetes as either monotherapy or in combination. The FDA approved dapagliflozin in October 2019 for the reduction of heart failure hospitalization risk in patients with type 2 diabetes and cardiovascular risk factors.
“Farxiga is well established in the treatment of type 2 diabetes and this Priority Review shows its potential to also impact millions of patients with heart failure. If approved, Farxiga will be the first and only medicine of its kind indicated to treat patients with heart failure,” said Mene Pangalos, executive vice president of biopharmaceutical research and development at AstraZeneca.
Find the full press release on the AstraZeneca website.
The Food and Drug Administration has accepted a supplemental New Drug Application and granted Priority Review for dapagliflozin (Farxiga) for the reduction of risk of cardiovascular death or worsening of heart failure in adult patients with heart failure with reduced ejection fraction (HFrEF).
The application was based on results from the landmark, phase 3 DAPA-HF trial, published in September 2019 in the New England Journal of Medicine. The study showed that dapagliflozin plus standard care reduced the incidence of cardiovascular death and worsening of heart failure versus placebo in patients with HFrEF.
Dapagliflozin was granted Fast Track designation for heart failure by the FDA in September 2019. In August 2019, the FDA also granted Fast Track designation to dapagliflozin for the delayed progression of renal failure and prevention of cardiovascular and renal death in patients with chronic kidney disease.
The drug is currently indicated for the improvement of glycemic control in adults with type 2 diabetes as either monotherapy or in combination. The FDA approved dapagliflozin in October 2019 for the reduction of heart failure hospitalization risk in patients with type 2 diabetes and cardiovascular risk factors.
“Farxiga is well established in the treatment of type 2 diabetes and this Priority Review shows its potential to also impact millions of patients with heart failure. If approved, Farxiga will be the first and only medicine of its kind indicated to treat patients with heart failure,” said Mene Pangalos, executive vice president of biopharmaceutical research and development at AstraZeneca.
Find the full press release on the AstraZeneca website.
The Food and Drug Administration has accepted a supplemental New Drug Application and granted Priority Review for dapagliflozin (Farxiga) for the reduction of risk of cardiovascular death or worsening of heart failure in adult patients with heart failure with reduced ejection fraction (HFrEF).
The application was based on results from the landmark, phase 3 DAPA-HF trial, published in September 2019 in the New England Journal of Medicine. The study showed that dapagliflozin plus standard care reduced the incidence of cardiovascular death and worsening of heart failure versus placebo in patients with HFrEF.
Dapagliflozin was granted Fast Track designation for heart failure by the FDA in September 2019. In August 2019, the FDA also granted Fast Track designation to dapagliflozin for the delayed progression of renal failure and prevention of cardiovascular and renal death in patients with chronic kidney disease.
The drug is currently indicated for the improvement of glycemic control in adults with type 2 diabetes as either monotherapy or in combination. The FDA approved dapagliflozin in October 2019 for the reduction of heart failure hospitalization risk in patients with type 2 diabetes and cardiovascular risk factors.
“Farxiga is well established in the treatment of type 2 diabetes and this Priority Review shows its potential to also impact millions of patients with heart failure. If approved, Farxiga will be the first and only medicine of its kind indicated to treat patients with heart failure,” said Mene Pangalos, executive vice president of biopharmaceutical research and development at AstraZeneca.
Find the full press release on the AstraZeneca website.
SGLT2 inhibitors for diabetes safe, effective in older adults
BUSAN, SOUTH KOREA – new research suggests.
Findings from a real-world observational study of 50 older adults with type 2 diabetes were recently presented at the International Diabetes Federation congress by Carlos Trescoli-Serrano, MD, of Hospital Universitario de la Ribera, Valencia, Spain.
“The results are quite similar to those of younger people. … In a selected population they are safe. It doesn’t matter if patients are older or younger. You have to review the patients for complications,” Dr. Trescoli-Serrano said in an interview.
Asked to comment, session moderator Samuel Dagogo-Jack, MD, said: “We need more and more studies in older people for reassurance. The elderly have impaired kidneys, and these drugs depend on kidney filtration. It’s good to have data on elderly patients in the real world.”
Most had comorbidities
The 50 adults were a mean age of 67 years, and the oldest was 81 years. They had a mean diabetes duration of 12.5 years, and 40% were women. They had all been taking SGLT2 inhibitors for more than 3 years (mean 43.9 months) during 2015-2019.
At baseline, most (75%) were also taking metformin, 45% also took sulfonylureas, 37% dipeptidyl peptidase-4 (DPP-4) inhibitors, and 36% insulin.
Most (81%) also had hypertension, half (51%) had hypercholesterolemia, a third (33%) had obesity, and 32% had a previous cardiovascular event.
With SGLT2-inhibitor treatment, the average hemoglobin A1c level dropped from 8.5% to 7.3% (P less than .01), body weight was reduced from 91.0 kg to 84.7 kg (P less than .01), systolic blood pressure from 134.5 mm Hg to 130.4 mm Hg (P = .02), and diastolic blood pressure from 76.2 mm Hg to 73.3 mm Hg (P = .04).
This effect on blood pressure “should be considered” because it means that “antihypertensive treatment might need to be reviewed,” Dr. Trescoli-Serrano commented.
There were no significant changes in estimated glomerular filtration rate (eGFR), microalbuminuria, lipid profile, hematocrit, or heart rate, although there were positive trends in both renal function and lipid profiles.
No patient had a fall, volume depletion symptoms, or diabetic ketoacidosis. However, 38% of patients were treated for urinary-genital infections, and 8% had to stop taking the SGLT2 inhibitor because of such infections.
That percentage seemed unusually high and was “an outlier, not the general experience,” commented Dr. Dagogo-Jack, chief of the Division of Endocrinology, Diabetes and Metabolism at the University of Tennessee Health Science Center, Memphis. He noted that infections with SGLT2 inhibitors are more often genital fungal than urinary tract infections, but the latter are more common in people with diabetes overall, and the study wasn’t randomized, so this might explain the finding.
New nonfatal cardiovascular events occurred in 22% of the patients, mainly cerebrovascular disease during the treatment period. Of those, 66% had had a previous cardiovascular event prior to starting on SGLT2 inhibitors.
Severe hypoglycemia was recorded in one patient, who was also taking insulin. Overall 10% died, mainly because of neoplastic causes.
“Long-term treatment with SGLT2 inhibitors are safe and effective when added to not-well-controlled elderly type 2 diabetes patients in a real-world experience,” Dr. Trescoli-Serrano concluded.
Dr. Dagogo-Jack is a consultant for Merck, Janssen, and Sanofi and owns stock in Dance Pharma and Jana Care.
A version of this story originally appeared on Medscape.com.
BUSAN, SOUTH KOREA – new research suggests.
Findings from a real-world observational study of 50 older adults with type 2 diabetes were recently presented at the International Diabetes Federation congress by Carlos Trescoli-Serrano, MD, of Hospital Universitario de la Ribera, Valencia, Spain.
“The results are quite similar to those of younger people. … In a selected population they are safe. It doesn’t matter if patients are older or younger. You have to review the patients for complications,” Dr. Trescoli-Serrano said in an interview.
Asked to comment, session moderator Samuel Dagogo-Jack, MD, said: “We need more and more studies in older people for reassurance. The elderly have impaired kidneys, and these drugs depend on kidney filtration. It’s good to have data on elderly patients in the real world.”
Most had comorbidities
The 50 adults were a mean age of 67 years, and the oldest was 81 years. They had a mean diabetes duration of 12.5 years, and 40% were women. They had all been taking SGLT2 inhibitors for more than 3 years (mean 43.9 months) during 2015-2019.
At baseline, most (75%) were also taking metformin, 45% also took sulfonylureas, 37% dipeptidyl peptidase-4 (DPP-4) inhibitors, and 36% insulin.
Most (81%) also had hypertension, half (51%) had hypercholesterolemia, a third (33%) had obesity, and 32% had a previous cardiovascular event.
With SGLT2-inhibitor treatment, the average hemoglobin A1c level dropped from 8.5% to 7.3% (P less than .01), body weight was reduced from 91.0 kg to 84.7 kg (P less than .01), systolic blood pressure from 134.5 mm Hg to 130.4 mm Hg (P = .02), and diastolic blood pressure from 76.2 mm Hg to 73.3 mm Hg (P = .04).
This effect on blood pressure “should be considered” because it means that “antihypertensive treatment might need to be reviewed,” Dr. Trescoli-Serrano commented.
There were no significant changes in estimated glomerular filtration rate (eGFR), microalbuminuria, lipid profile, hematocrit, or heart rate, although there were positive trends in both renal function and lipid profiles.
No patient had a fall, volume depletion symptoms, or diabetic ketoacidosis. However, 38% of patients were treated for urinary-genital infections, and 8% had to stop taking the SGLT2 inhibitor because of such infections.
That percentage seemed unusually high and was “an outlier, not the general experience,” commented Dr. Dagogo-Jack, chief of the Division of Endocrinology, Diabetes and Metabolism at the University of Tennessee Health Science Center, Memphis. He noted that infections with SGLT2 inhibitors are more often genital fungal than urinary tract infections, but the latter are more common in people with diabetes overall, and the study wasn’t randomized, so this might explain the finding.
New nonfatal cardiovascular events occurred in 22% of the patients, mainly cerebrovascular disease during the treatment period. Of those, 66% had had a previous cardiovascular event prior to starting on SGLT2 inhibitors.
Severe hypoglycemia was recorded in one patient, who was also taking insulin. Overall 10% died, mainly because of neoplastic causes.
“Long-term treatment with SGLT2 inhibitors are safe and effective when added to not-well-controlled elderly type 2 diabetes patients in a real-world experience,” Dr. Trescoli-Serrano concluded.
Dr. Dagogo-Jack is a consultant for Merck, Janssen, and Sanofi and owns stock in Dance Pharma and Jana Care.
A version of this story originally appeared on Medscape.com.
BUSAN, SOUTH KOREA – new research suggests.
Findings from a real-world observational study of 50 older adults with type 2 diabetes were recently presented at the International Diabetes Federation congress by Carlos Trescoli-Serrano, MD, of Hospital Universitario de la Ribera, Valencia, Spain.
“The results are quite similar to those of younger people. … In a selected population they are safe. It doesn’t matter if patients are older or younger. You have to review the patients for complications,” Dr. Trescoli-Serrano said in an interview.
Asked to comment, session moderator Samuel Dagogo-Jack, MD, said: “We need more and more studies in older people for reassurance. The elderly have impaired kidneys, and these drugs depend on kidney filtration. It’s good to have data on elderly patients in the real world.”
Most had comorbidities
The 50 adults were a mean age of 67 years, and the oldest was 81 years. They had a mean diabetes duration of 12.5 years, and 40% were women. They had all been taking SGLT2 inhibitors for more than 3 years (mean 43.9 months) during 2015-2019.
At baseline, most (75%) were also taking metformin, 45% also took sulfonylureas, 37% dipeptidyl peptidase-4 (DPP-4) inhibitors, and 36% insulin.
Most (81%) also had hypertension, half (51%) had hypercholesterolemia, a third (33%) had obesity, and 32% had a previous cardiovascular event.
With SGLT2-inhibitor treatment, the average hemoglobin A1c level dropped from 8.5% to 7.3% (P less than .01), body weight was reduced from 91.0 kg to 84.7 kg (P less than .01), systolic blood pressure from 134.5 mm Hg to 130.4 mm Hg (P = .02), and diastolic blood pressure from 76.2 mm Hg to 73.3 mm Hg (P = .04).
This effect on blood pressure “should be considered” because it means that “antihypertensive treatment might need to be reviewed,” Dr. Trescoli-Serrano commented.
There were no significant changes in estimated glomerular filtration rate (eGFR), microalbuminuria, lipid profile, hematocrit, or heart rate, although there were positive trends in both renal function and lipid profiles.
No patient had a fall, volume depletion symptoms, or diabetic ketoacidosis. However, 38% of patients were treated for urinary-genital infections, and 8% had to stop taking the SGLT2 inhibitor because of such infections.
That percentage seemed unusually high and was “an outlier, not the general experience,” commented Dr. Dagogo-Jack, chief of the Division of Endocrinology, Diabetes and Metabolism at the University of Tennessee Health Science Center, Memphis. He noted that infections with SGLT2 inhibitors are more often genital fungal than urinary tract infections, but the latter are more common in people with diabetes overall, and the study wasn’t randomized, so this might explain the finding.
New nonfatal cardiovascular events occurred in 22% of the patients, mainly cerebrovascular disease during the treatment period. Of those, 66% had had a previous cardiovascular event prior to starting on SGLT2 inhibitors.
Severe hypoglycemia was recorded in one patient, who was also taking insulin. Overall 10% died, mainly because of neoplastic causes.
“Long-term treatment with SGLT2 inhibitors are safe and effective when added to not-well-controlled elderly type 2 diabetes patients in a real-world experience,” Dr. Trescoli-Serrano concluded.
Dr. Dagogo-Jack is a consultant for Merck, Janssen, and Sanofi and owns stock in Dance Pharma and Jana Care.
A version of this story originally appeared on Medscape.com.
Top picks for online diabetes information for doctors and patients
BUSAN, SOUTH KOREA – says endocrinologist Irl B. Hirsch, MD, professor of medicine and diabetes treatment and teaching chair at the University of Washington, Seattle.
Speaking at the recent International Diabetes Federation Congress, Dr. Hirsch offered the international audience a list of sites he considers reliable and helpful, but with the caveat that “this is by no means a complete list, but these are some of my favorites.”
Session moderator David M. Maahs, MD, PhD, chief of pediatric endocrinology at Stanford (Calif.) University, said in an interview that it is now pointless to try to tell patients not to look things up online. “Everyone is going to go on the Internet, so point people in the right direction for reliable information,” he advised.
For general diabetes information, Dr. Hirsch said society websites are a good place for clinicians and patients to start. Among the best of these, he said, are:
- American Diabetes Association (ADA).
- Diabetes Australia.
- Diabetes UK.
- European Association for the Study of Diabetes (EASD).
- International Diabetes Federation (IDF).
- JDRF (type 1 diabetes).
Sites for type 1 diabetes
He pointed out in his talk that he was able to find many more reliable sites for type 1 diabetes than for type 2 diabetes. Among his top picks was the Children with Diabetes (CWD) website, which he said was “an outstanding site for type 1 diabetes for children, parents, grandparents, and also adults with type 1 diabetes.” Its content includes up-to-date information about all aspects of type 1 diabetes research, frequent polls of common questions, and discussion forums.
“It’s not just the United States. People from all over the world are looking at this site,” Dr. Hirsch noted.
For 2 decades, the CWD has sponsored the Friends for Life conference, which takes place in Orlando every July. The event is now attended by around 3,000 children and young adults with type 1 diabetes and their family members, he noted.
Dr. Maahs seconded Dr. Hirsch’s CWD recommendation. “They’ve continued to have a wonderful website, a great source of information. The conference is great. They’ll put you in touch with people in your area.”
Another good type 1 diabetes site for patients and families is that of the JDRF (formerly the Juvenile Diabetes Research Foundation), which provides “an outstanding review of type 1 diabetes research and social action,” Dr. Hirsch commented. In addition to the main site, there are also regional JDRF sites in Australia, the United Kingdom, and Canada.
Beyond Type 1 is part of a network that also includes Beyond Type 2 and Spanish-language sites for both Beyond Type 1 and Beyond Type 2. The sites feature news, stories, self-help, and resources.
The International Society for Pediatric and Adolescent Diabetes (ISPAD) has a site for clinicians and families with type 1 diabetes, according to Dr. Hirsch. It provides information about events, resources, and guidelines. A recent article, for example, addresses fasting during Ramadan or young people with diabetes.
Dr. Maahs, who is secretary general of ISPAD and edited the organization’s 2018 Clinical Practice Consensus Guidelines, noted that all of the clinical guidelines and patient education materials are free on the site, as are conference presentations from the past 3 years. A lot of the material is also available in different languages, he noted.
He also pointed out that ISPAD’s recommendations for pediatric diabetes are mostly in line with that of the ADA, but they include far more information – 25 chapters versus just one ADA chapter. Also, in 2018, ISPAD lowered its A1c target for children from 7.5% to 7.0%, which aligns with Scandinavian but not U.S. recommendations.
In addition to the type 1 diabetes sites that Dr. Hirsch listed, Dr. Maahs added the T1D Exchange online community site Glu, which he said was a good patient advocacy site.
Sites for type 2 diabetes
Dr. Hirsch recommended several sites for patients with type 2 diabetes, including:
- The Johns Hopkins Patient Guide to Diabetes, one of his favorite type 2 diabetes sites because of its “artistry, the graphics – you get it from just looking at the pictures. There’s a tech corner, videos, and patient stories. There’s just a lot here for patients.”
- Diabetes Sisters, specifically for women with diabetes.
- Diabetes Strong, which focuses on exercise.
- Wildly Fluctuating, with topics “from humor to serious stuff to miscellaneous musings on the diabetes news of the week by a type 2 diabetes patient/expert.”
Sites for clinicians
For clinicians, Dr. Hirsch said the following sites provide free and up-to-date information on the management of type 2 diabetes (some also include type 1 diabetes):
- ADA/EASD Standards of Care.
- Diabetes Canada 2018 Guidelines.
- American Association of Clinical Endocrinologists Type 2 Diabetes Management Algorithm.
- UK National Institute for Health and Care Excellence, which Dr. Hirsch called “extensive evidence-based guidelines. They really dig into the evidence as much, if not more, than most of the national standards of care around the world.”
- Clinical Diabetes, an ADA journal that provides “outstanding articles geared for nonspecialists free to clinicians online 6 months after publication.” It includes some primary data articles, but it is mostly review, he noted.
Regional sites
Dr. Hirsch included information about regional sites as well:
- Dr. Mohan’s Diabetes Specialties Centre, “a very good site for those living in India.”
- HealthDirect in Australia.
- Diabetes UK.
Dr. Hirsch is a consultant for Abbott Diabetes Care, Roche, and Bigfoot; conducts research for Medtronic; and is an editor on diabetes for UpToDate. Dr. Maahs has received research support from the National Institutes of Health, JDRF, National Science Foundation, and Leona M. and Harry B. Helmsley Charitable Trust and has consulted for Abbott, Helmsley, Sanofi, Novo Nordisk, Eli Lilly, and Insulet.
A version of this story originally appeared on Medscape.com.
BUSAN, SOUTH KOREA – says endocrinologist Irl B. Hirsch, MD, professor of medicine and diabetes treatment and teaching chair at the University of Washington, Seattle.
Speaking at the recent International Diabetes Federation Congress, Dr. Hirsch offered the international audience a list of sites he considers reliable and helpful, but with the caveat that “this is by no means a complete list, but these are some of my favorites.”
Session moderator David M. Maahs, MD, PhD, chief of pediatric endocrinology at Stanford (Calif.) University, said in an interview that it is now pointless to try to tell patients not to look things up online. “Everyone is going to go on the Internet, so point people in the right direction for reliable information,” he advised.
For general diabetes information, Dr. Hirsch said society websites are a good place for clinicians and patients to start. Among the best of these, he said, are:
- American Diabetes Association (ADA).
- Diabetes Australia.
- Diabetes UK.
- European Association for the Study of Diabetes (EASD).
- International Diabetes Federation (IDF).
- JDRF (type 1 diabetes).
Sites for type 1 diabetes
He pointed out in his talk that he was able to find many more reliable sites for type 1 diabetes than for type 2 diabetes. Among his top picks was the Children with Diabetes (CWD) website, which he said was “an outstanding site for type 1 diabetes for children, parents, grandparents, and also adults with type 1 diabetes.” Its content includes up-to-date information about all aspects of type 1 diabetes research, frequent polls of common questions, and discussion forums.
“It’s not just the United States. People from all over the world are looking at this site,” Dr. Hirsch noted.
For 2 decades, the CWD has sponsored the Friends for Life conference, which takes place in Orlando every July. The event is now attended by around 3,000 children and young adults with type 1 diabetes and their family members, he noted.
Dr. Maahs seconded Dr. Hirsch’s CWD recommendation. “They’ve continued to have a wonderful website, a great source of information. The conference is great. They’ll put you in touch with people in your area.”
Another good type 1 diabetes site for patients and families is that of the JDRF (formerly the Juvenile Diabetes Research Foundation), which provides “an outstanding review of type 1 diabetes research and social action,” Dr. Hirsch commented. In addition to the main site, there are also regional JDRF sites in Australia, the United Kingdom, and Canada.
Beyond Type 1 is part of a network that also includes Beyond Type 2 and Spanish-language sites for both Beyond Type 1 and Beyond Type 2. The sites feature news, stories, self-help, and resources.
The International Society for Pediatric and Adolescent Diabetes (ISPAD) has a site for clinicians and families with type 1 diabetes, according to Dr. Hirsch. It provides information about events, resources, and guidelines. A recent article, for example, addresses fasting during Ramadan or young people with diabetes.
Dr. Maahs, who is secretary general of ISPAD and edited the organization’s 2018 Clinical Practice Consensus Guidelines, noted that all of the clinical guidelines and patient education materials are free on the site, as are conference presentations from the past 3 years. A lot of the material is also available in different languages, he noted.
He also pointed out that ISPAD’s recommendations for pediatric diabetes are mostly in line with that of the ADA, but they include far more information – 25 chapters versus just one ADA chapter. Also, in 2018, ISPAD lowered its A1c target for children from 7.5% to 7.0%, which aligns with Scandinavian but not U.S. recommendations.
In addition to the type 1 diabetes sites that Dr. Hirsch listed, Dr. Maahs added the T1D Exchange online community site Glu, which he said was a good patient advocacy site.
Sites for type 2 diabetes
Dr. Hirsch recommended several sites for patients with type 2 diabetes, including:
- The Johns Hopkins Patient Guide to Diabetes, one of his favorite type 2 diabetes sites because of its “artistry, the graphics – you get it from just looking at the pictures. There’s a tech corner, videos, and patient stories. There’s just a lot here for patients.”
- Diabetes Sisters, specifically for women with diabetes.
- Diabetes Strong, which focuses on exercise.
- Wildly Fluctuating, with topics “from humor to serious stuff to miscellaneous musings on the diabetes news of the week by a type 2 diabetes patient/expert.”
Sites for clinicians
For clinicians, Dr. Hirsch said the following sites provide free and up-to-date information on the management of type 2 diabetes (some also include type 1 diabetes):
- ADA/EASD Standards of Care.
- Diabetes Canada 2018 Guidelines.
- American Association of Clinical Endocrinologists Type 2 Diabetes Management Algorithm.
- UK National Institute for Health and Care Excellence, which Dr. Hirsch called “extensive evidence-based guidelines. They really dig into the evidence as much, if not more, than most of the national standards of care around the world.”
- Clinical Diabetes, an ADA journal that provides “outstanding articles geared for nonspecialists free to clinicians online 6 months after publication.” It includes some primary data articles, but it is mostly review, he noted.
Regional sites
Dr. Hirsch included information about regional sites as well:
- Dr. Mohan’s Diabetes Specialties Centre, “a very good site for those living in India.”
- HealthDirect in Australia.
- Diabetes UK.
Dr. Hirsch is a consultant for Abbott Diabetes Care, Roche, and Bigfoot; conducts research for Medtronic; and is an editor on diabetes for UpToDate. Dr. Maahs has received research support from the National Institutes of Health, JDRF, National Science Foundation, and Leona M. and Harry B. Helmsley Charitable Trust and has consulted for Abbott, Helmsley, Sanofi, Novo Nordisk, Eli Lilly, and Insulet.
A version of this story originally appeared on Medscape.com.
BUSAN, SOUTH KOREA – says endocrinologist Irl B. Hirsch, MD, professor of medicine and diabetes treatment and teaching chair at the University of Washington, Seattle.
Speaking at the recent International Diabetes Federation Congress, Dr. Hirsch offered the international audience a list of sites he considers reliable and helpful, but with the caveat that “this is by no means a complete list, but these are some of my favorites.”
Session moderator David M. Maahs, MD, PhD, chief of pediatric endocrinology at Stanford (Calif.) University, said in an interview that it is now pointless to try to tell patients not to look things up online. “Everyone is going to go on the Internet, so point people in the right direction for reliable information,” he advised.
For general diabetes information, Dr. Hirsch said society websites are a good place for clinicians and patients to start. Among the best of these, he said, are:
- American Diabetes Association (ADA).
- Diabetes Australia.
- Diabetes UK.
- European Association for the Study of Diabetes (EASD).
- International Diabetes Federation (IDF).
- JDRF (type 1 diabetes).
Sites for type 1 diabetes
He pointed out in his talk that he was able to find many more reliable sites for type 1 diabetes than for type 2 diabetes. Among his top picks was the Children with Diabetes (CWD) website, which he said was “an outstanding site for type 1 diabetes for children, parents, grandparents, and also adults with type 1 diabetes.” Its content includes up-to-date information about all aspects of type 1 diabetes research, frequent polls of common questions, and discussion forums.
“It’s not just the United States. People from all over the world are looking at this site,” Dr. Hirsch noted.
For 2 decades, the CWD has sponsored the Friends for Life conference, which takes place in Orlando every July. The event is now attended by around 3,000 children and young adults with type 1 diabetes and their family members, he noted.
Dr. Maahs seconded Dr. Hirsch’s CWD recommendation. “They’ve continued to have a wonderful website, a great source of information. The conference is great. They’ll put you in touch with people in your area.”
Another good type 1 diabetes site for patients and families is that of the JDRF (formerly the Juvenile Diabetes Research Foundation), which provides “an outstanding review of type 1 diabetes research and social action,” Dr. Hirsch commented. In addition to the main site, there are also regional JDRF sites in Australia, the United Kingdom, and Canada.
Beyond Type 1 is part of a network that also includes Beyond Type 2 and Spanish-language sites for both Beyond Type 1 and Beyond Type 2. The sites feature news, stories, self-help, and resources.
The International Society for Pediatric and Adolescent Diabetes (ISPAD) has a site for clinicians and families with type 1 diabetes, according to Dr. Hirsch. It provides information about events, resources, and guidelines. A recent article, for example, addresses fasting during Ramadan or young people with diabetes.
Dr. Maahs, who is secretary general of ISPAD and edited the organization’s 2018 Clinical Practice Consensus Guidelines, noted that all of the clinical guidelines and patient education materials are free on the site, as are conference presentations from the past 3 years. A lot of the material is also available in different languages, he noted.
He also pointed out that ISPAD’s recommendations for pediatric diabetes are mostly in line with that of the ADA, but they include far more information – 25 chapters versus just one ADA chapter. Also, in 2018, ISPAD lowered its A1c target for children from 7.5% to 7.0%, which aligns with Scandinavian but not U.S. recommendations.
In addition to the type 1 diabetes sites that Dr. Hirsch listed, Dr. Maahs added the T1D Exchange online community site Glu, which he said was a good patient advocacy site.
Sites for type 2 diabetes
Dr. Hirsch recommended several sites for patients with type 2 diabetes, including:
- The Johns Hopkins Patient Guide to Diabetes, one of his favorite type 2 diabetes sites because of its “artistry, the graphics – you get it from just looking at the pictures. There’s a tech corner, videos, and patient stories. There’s just a lot here for patients.”
- Diabetes Sisters, specifically for women with diabetes.
- Diabetes Strong, which focuses on exercise.
- Wildly Fluctuating, with topics “from humor to serious stuff to miscellaneous musings on the diabetes news of the week by a type 2 diabetes patient/expert.”
Sites for clinicians
For clinicians, Dr. Hirsch said the following sites provide free and up-to-date information on the management of type 2 diabetes (some also include type 1 diabetes):
- ADA/EASD Standards of Care.
- Diabetes Canada 2018 Guidelines.
- American Association of Clinical Endocrinologists Type 2 Diabetes Management Algorithm.
- UK National Institute for Health and Care Excellence, which Dr. Hirsch called “extensive evidence-based guidelines. They really dig into the evidence as much, if not more, than most of the national standards of care around the world.”
- Clinical Diabetes, an ADA journal that provides “outstanding articles geared for nonspecialists free to clinicians online 6 months after publication.” It includes some primary data articles, but it is mostly review, he noted.
Regional sites
Dr. Hirsch included information about regional sites as well:
- Dr. Mohan’s Diabetes Specialties Centre, “a very good site for those living in India.”
- HealthDirect in Australia.
- Diabetes UK.
Dr. Hirsch is a consultant for Abbott Diabetes Care, Roche, and Bigfoot; conducts research for Medtronic; and is an editor on diabetes for UpToDate. Dr. Maahs has received research support from the National Institutes of Health, JDRF, National Science Foundation, and Leona M. and Harry B. Helmsley Charitable Trust and has consulted for Abbott, Helmsley, Sanofi, Novo Nordisk, Eli Lilly, and Insulet.
A version of this story originally appeared on Medscape.com.
Can insulin plus metformin improve pregnancy outcomes in women with type 2 diabetes?
WASHINGTON – Insulin is the preferred agent for type 2 diabetes in pregnant women, yet about a third of pregnancies still have an adverse outcome, according Kim Boggess, MD, who spoke at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.
“We are not where we need to be,” said Dr. Boggess, who is leading a trial that brings metformin, the first-line agent for type 2 diabetes outside of pregnancy, back into the picture for pregnant women – as an add-on to insulin.
It is an interesting twist, because pregnant women taking metformin for preexisting type 2 or gestational diabetes have been shown in some studies to require supplemental insulin, more than occasionally, to achieve target glycemic control.
This was the case in a small, randomized, controlled trial at Dr. Boggess’ institution, the University of North Carolina at Chapel Hill, in which 43% of pregnant women with type 2 diabetes who were assigned to metformin required supplemental insulin (Am J Perinatol. 2013;30[6]:483-90). (0% vs. 36%, respectively) and fewer reports of glucose values less than 60 mg/dL (7.1% vs. 50%).
“I don’t consider this [need for supplemental insulin] ‘metformin failure,’ because studies that use metformin as monotherapy and that [show some patients] ultimately requiring insulin support ... also show that these women need less insulin,” she said. “What’s the risk of insulin alone? Hypoglycemia. So using less insulin could be a good thing.”
Other research suggests there may be less maternal weight gain, less neonatal hypoglycemia, fewer neonatal complications, and improved maternal glycemic control in patients treated with metformin, alone or with add-on insulin, than with insulin alone. “We’re starting to get a sense in the literature that, at least in the [pregnant] population with type 2 diabetes, there may be a role for metformin,” said Dr. Boggess, professor and program director for maternal-fetal medicine at the university.
Currently, the multisite MOMPOD trial (Medical Optimization of Management of T2DM Complicating Pregnancy) is randomizing 950 women to insulin plus 1,000 mg metformin twice daily or insulin plus placebo. The primary outcome of the trial is a composite of pregnancy loss, preterm birth, birth injury, neonatal hypoglycemia, or hyperbilirubinemia. Infant fat mass (within 72 hours of birth) is a secondary outcome, along with maternal safety and maternal side effects.
The MiTy (Metformin in Women with T2DM in Pregnancy) trial in Canada, with similar randomization arms and outcomes measures, is completed and undergoing analysis. “Hopefully we’ll [soon] be able to say whether the addition of adjuvant metformin to insulin to treat type 2 diabetes brings the perinatal adverse outcome rate down from 30%,” said Dr. Boggess.
Metformin is the recommended first-line agent for type 2 diabetes in nonpregnant adults. But during pregnancy, insulin, which does not cross the placenta, is the preferred agent, according to recommendations of the American Diabetes Association and the American College of Obstetricians and Gynecologists, she noted. Lingering in the background is the fact that the long-term effects of in utero metformin exposure on offspring – and of exposure to any oral hypoglycemic agent – are unknown, she said*
A majority of the adverse pregnancy outcomes that occur in the context of type 2 diabetes involve macrosomia. “It’s a big deal,” Dr. Boggess said, that results in numerous maternal and infant risks and complications. “We also know that the in utero environment that contributes to, or causes, macrosomia predisposes to childhood obesity and obesity later on.”
Diabetes is the “leading risk factor” for adverse pregnancy outcomes today, said E. Albert Reece, MD, PhD, MBA, executive vice president for medical affairs at the University of Maryland, Baltimore, and the John Z. and Akiko K. Bowers distinguished professor and dean of the University of Maryland School of Medicine. In the United States, 11% of women aged 20 years and older have diabetes, and the disease affects more than 1% of all pregnancies, he said.
The MOMPOD trial is sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Boggess reported no conflicts of interest.
* This article was updated 1/2/2020.
WASHINGTON – Insulin is the preferred agent for type 2 diabetes in pregnant women, yet about a third of pregnancies still have an adverse outcome, according Kim Boggess, MD, who spoke at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.
“We are not where we need to be,” said Dr. Boggess, who is leading a trial that brings metformin, the first-line agent for type 2 diabetes outside of pregnancy, back into the picture for pregnant women – as an add-on to insulin.
It is an interesting twist, because pregnant women taking metformin for preexisting type 2 or gestational diabetes have been shown in some studies to require supplemental insulin, more than occasionally, to achieve target glycemic control.
This was the case in a small, randomized, controlled trial at Dr. Boggess’ institution, the University of North Carolina at Chapel Hill, in which 43% of pregnant women with type 2 diabetes who were assigned to metformin required supplemental insulin (Am J Perinatol. 2013;30[6]:483-90). (0% vs. 36%, respectively) and fewer reports of glucose values less than 60 mg/dL (7.1% vs. 50%).
“I don’t consider this [need for supplemental insulin] ‘metformin failure,’ because studies that use metformin as monotherapy and that [show some patients] ultimately requiring insulin support ... also show that these women need less insulin,” she said. “What’s the risk of insulin alone? Hypoglycemia. So using less insulin could be a good thing.”
Other research suggests there may be less maternal weight gain, less neonatal hypoglycemia, fewer neonatal complications, and improved maternal glycemic control in patients treated with metformin, alone or with add-on insulin, than with insulin alone. “We’re starting to get a sense in the literature that, at least in the [pregnant] population with type 2 diabetes, there may be a role for metformin,” said Dr. Boggess, professor and program director for maternal-fetal medicine at the university.
Currently, the multisite MOMPOD trial (Medical Optimization of Management of T2DM Complicating Pregnancy) is randomizing 950 women to insulin plus 1,000 mg metformin twice daily or insulin plus placebo. The primary outcome of the trial is a composite of pregnancy loss, preterm birth, birth injury, neonatal hypoglycemia, or hyperbilirubinemia. Infant fat mass (within 72 hours of birth) is a secondary outcome, along with maternal safety and maternal side effects.
The MiTy (Metformin in Women with T2DM in Pregnancy) trial in Canada, with similar randomization arms and outcomes measures, is completed and undergoing analysis. “Hopefully we’ll [soon] be able to say whether the addition of adjuvant metformin to insulin to treat type 2 diabetes brings the perinatal adverse outcome rate down from 30%,” said Dr. Boggess.
Metformin is the recommended first-line agent for type 2 diabetes in nonpregnant adults. But during pregnancy, insulin, which does not cross the placenta, is the preferred agent, according to recommendations of the American Diabetes Association and the American College of Obstetricians and Gynecologists, she noted. Lingering in the background is the fact that the long-term effects of in utero metformin exposure on offspring – and of exposure to any oral hypoglycemic agent – are unknown, she said*
A majority of the adverse pregnancy outcomes that occur in the context of type 2 diabetes involve macrosomia. “It’s a big deal,” Dr. Boggess said, that results in numerous maternal and infant risks and complications. “We also know that the in utero environment that contributes to, or causes, macrosomia predisposes to childhood obesity and obesity later on.”
Diabetes is the “leading risk factor” for adverse pregnancy outcomes today, said E. Albert Reece, MD, PhD, MBA, executive vice president for medical affairs at the University of Maryland, Baltimore, and the John Z. and Akiko K. Bowers distinguished professor and dean of the University of Maryland School of Medicine. In the United States, 11% of women aged 20 years and older have diabetes, and the disease affects more than 1% of all pregnancies, he said.
The MOMPOD trial is sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Boggess reported no conflicts of interest.
* This article was updated 1/2/2020.
WASHINGTON – Insulin is the preferred agent for type 2 diabetes in pregnant women, yet about a third of pregnancies still have an adverse outcome, according Kim Boggess, MD, who spoke at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.
“We are not where we need to be,” said Dr. Boggess, who is leading a trial that brings metformin, the first-line agent for type 2 diabetes outside of pregnancy, back into the picture for pregnant women – as an add-on to insulin.
It is an interesting twist, because pregnant women taking metformin for preexisting type 2 or gestational diabetes have been shown in some studies to require supplemental insulin, more than occasionally, to achieve target glycemic control.
This was the case in a small, randomized, controlled trial at Dr. Boggess’ institution, the University of North Carolina at Chapel Hill, in which 43% of pregnant women with type 2 diabetes who were assigned to metformin required supplemental insulin (Am J Perinatol. 2013;30[6]:483-90). (0% vs. 36%, respectively) and fewer reports of glucose values less than 60 mg/dL (7.1% vs. 50%).
“I don’t consider this [need for supplemental insulin] ‘metformin failure,’ because studies that use metformin as monotherapy and that [show some patients] ultimately requiring insulin support ... also show that these women need less insulin,” she said. “What’s the risk of insulin alone? Hypoglycemia. So using less insulin could be a good thing.”
Other research suggests there may be less maternal weight gain, less neonatal hypoglycemia, fewer neonatal complications, and improved maternal glycemic control in patients treated with metformin, alone or with add-on insulin, than with insulin alone. “We’re starting to get a sense in the literature that, at least in the [pregnant] population with type 2 diabetes, there may be a role for metformin,” said Dr. Boggess, professor and program director for maternal-fetal medicine at the university.
Currently, the multisite MOMPOD trial (Medical Optimization of Management of T2DM Complicating Pregnancy) is randomizing 950 women to insulin plus 1,000 mg metformin twice daily or insulin plus placebo. The primary outcome of the trial is a composite of pregnancy loss, preterm birth, birth injury, neonatal hypoglycemia, or hyperbilirubinemia. Infant fat mass (within 72 hours of birth) is a secondary outcome, along with maternal safety and maternal side effects.
The MiTy (Metformin in Women with T2DM in Pregnancy) trial in Canada, with similar randomization arms and outcomes measures, is completed and undergoing analysis. “Hopefully we’ll [soon] be able to say whether the addition of adjuvant metformin to insulin to treat type 2 diabetes brings the perinatal adverse outcome rate down from 30%,” said Dr. Boggess.
Metformin is the recommended first-line agent for type 2 diabetes in nonpregnant adults. But during pregnancy, insulin, which does not cross the placenta, is the preferred agent, according to recommendations of the American Diabetes Association and the American College of Obstetricians and Gynecologists, she noted. Lingering in the background is the fact that the long-term effects of in utero metformin exposure on offspring – and of exposure to any oral hypoglycemic agent – are unknown, she said*
A majority of the adverse pregnancy outcomes that occur in the context of type 2 diabetes involve macrosomia. “It’s a big deal,” Dr. Boggess said, that results in numerous maternal and infant risks and complications. “We also know that the in utero environment that contributes to, or causes, macrosomia predisposes to childhood obesity and obesity later on.”
Diabetes is the “leading risk factor” for adverse pregnancy outcomes today, said E. Albert Reece, MD, PhD, MBA, executive vice president for medical affairs at the University of Maryland, Baltimore, and the John Z. and Akiko K. Bowers distinguished professor and dean of the University of Maryland School of Medicine. In the United States, 11% of women aged 20 years and older have diabetes, and the disease affects more than 1% of all pregnancies, he said.
The MOMPOD trial is sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Boggess reported no conflicts of interest.
* This article was updated 1/2/2020.
REPORTING FROM DPSG-NA 2019
End ‘therapeutic nihilism’ in care of older diabetic patients, says expert
LOS ANGELES – In the opinion of Richard Pratley, MD, it’s time for diabetes treatment guidelines to evolve in light of accumulating data from cardiovascular outcome trials in type 2 diabetes.
“They have evolved for the general patient population, and this should apply to older individuals as well,” Dr. Pratley said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “My fear is, there is therapeutic nihilism, the idea that by the time someone is 75 years old, the horse is out of the barn and you’re not going to be able to impact outcomes with directed therapy. I don’t think that’s true. Our current treatment guidelines for the treatment of diabetes in older individuals remain focused on glycemic control. It’s not hyperglycemia that’s killing people; it’s heart disease and renal disease.”
According to data from the United Nations, about 12% of the global population is older than 60. By 2050, that number is expected to reach 20%, which will continue to drive an epidemic of diabetes in the near future. Dr. Pratley, medical director of AdventHealth Diabetes Institute in Orlando, pointed out that diabetes in older individuals is not a homogeneous condition. “There are many people in my clinic who had type 1 diabetes diagnosed as kids, but I also have patients who have adult-onset type 1 diabetes,” he said. “We also have type 2 patients who can be diagnosed in their 20s, 30s, or 40s, and there are people who are diagnosed in their 70s and 80s. Now we are learning that there are different subtypes of diabetes; so even type 2 diabetes is not a homogeneous condition. There are people who are more insulin resistant or have more of an insulin secretory defect, and there’s a special type of older-onset type 2 diabetes. When you consider all this in talking about diabetes treatments, about 30% of patients in the United States are diagnosed [when they are] over the age of 60, so this is an ongoing issue.”
Older adults with diabetes may have longstanding diabetes with associated microvascular and macrovascular complications, he continued, or they may have newly diagnosed diabetes with evidence of end organ complications at the time of presentation. Or, they may have newly diagnosed diabetes without evidence of complications. “Does this matter? It does,” Dr. Pratley said. “The things we worry about with all patients with diabetes are the microvascular complications, but I would argue that the macrovascular complications, particularly diabetic nephropathy, are things we should have a laser focus on, because they have high morbidity and mortality, especially in older individuals.”
There are more than 28 cardiovascular outcomes trials in patients with type 2 diabetes ongoing or completed, and involving eight classes of medications, with more than 200,000 planned participants, Dr. Pratley said. Of those participants, 90,000 are older than 65 years, and 30,000 are older than 75 years. “This is great,” he said. “Not only do these cardiovascular outcome studies give us a lot of information about the safety and efficacy of these drugs in the general population, we can now dig in to this specific patient population.” For example, in cardiovascular outcomes trials with dipeptidyl peptidase–4 (DPP-4) inhibitors, the mean age of patients was 65. About half of the patients were older than 65, and 10%-14% were older than 75.
Investigators in the SAVOR-TIMI 53 trial examined age in one of their subgroup analyses (Diabetes Care. 2015;38:1145-53). In that study with saxagliptin, among people older than 65 who received the study drug, the hazard ratio for major adverse cardiac events (MACE) was 0.92, compared with 1.15 for those younger than 65 (P value for interaction = .058). “So older people did great [on this drug],” Dr. Pratley said. “In fact, they had a bit of a decreased risk.” A similar association was seen in adults aged 75 years and older (HR, 1.01 in those younger than 75 years, vs. 0.95 in those aged 75 years and older; P value for interaction = .673). “This is telling us that saxagliptin is safe in the older population.”
In the EXAMINE trial, in which patients with type 2 diabetes who had had a recent acute coronary syndrome received either alogliptin or placebo, researchers conducted an analysis of patients older and younger than 65 (N Engl J Med. 2013;369:1327-35). They observed no significant interactions on the primary composite cardiovascular outcome in those younger than 65 (HR, 0.91) and those aged 65 and older (HR, 0.98).
Dr. Pratley noted that in cardiovascular outcome trials with sodium-glucose transporter 2 (SGLT2) inhibitors, the mean age of patients was 64, and 48%-50% of them were older than 65. In the EMPA-REG OUTCOME trial of empagliflozin, the hazard ratio for the primary cardiovascular outcome was 1.04 in patients younger than 65 and 0.71 in those aged 65 and older (P = .01; N Engl J Med, 2015;373:2117-28). “That was a significant interaction,” he said. In addition, the hazard ratio for cardiovascular death was 0.72 in those younger than 65, and 0.54 in those aged 65 and older (P = .21). “There was not a significant interaction here, but clearly there was some trending in the older patient population,” Dr. Pratley said.
In the LEADER study of liraglutide in patients with diabetes, the hazard ratio for the primary composite cardiovascular outcome was 0.87 in the overall population, 0.78 in patients younger than 60, and 0.90 in those aged 60 and older (P = 0.27; N Engl J Med. 2016;375:311-22). In a post hoc analysis that stratified LEADER patients into younger than 75 and 75 and older, the researchers observed a 31% reduction in the 75 and older population, compared with a 10% reduction in the younger population (P for interaction = .09; Ann Intern Med. 2019;170[6]:423-6). “This was driven largely by a decrease in nonfatal [myocardial infarction],” said Dr. Pratley, who was one of the study investigators. “But in patients who were 75 years and older, there was a 30% reduction in all-cause mortality in those treated with liraglutide, compared with 12% in those younger than 75 (P for interaction = .22). That interaction is not significant, but the theme here is that older populations do quite well.”
Based on such evidence, he said, In particular, SGLT2 inhibitors and certain GLP-1 receptor agonists may be associated with an additional benefit in older individuals with cardiovascular disease, “perhaps because they’re the ones at highest risk,” Dr. Pratley said. “But we need further studies to better identify those older individuals who may be at highest risk of adverse cardiovascular complications from diabetes and who might benefit from targeted therapies.”
Many questions remain unanswered in efforts to provide optimal care to older adults with diabetes. “One of the problems is being inclusive in the older patient population,” Dr. Pratley said. “We tried to do a study of frail older individuals looking at different treatments and policies. It was difficult to recruit frail older individuals, even though they routinely are treated with the drugs we study in healthier populations. We need to know how to enroll patients, and which investigators are going to do these trials. Who is going to support these trials? Pharma? The NIH?”
Then there’s the question of what appropriate outcomes are in older individuals. “I think we can agree that hemoglobin A1c is a surrogate of microvascular complications,” he said. “Do we need to be looking at outcomes like MACE, hospitalization for heart failure, death, progression of [chronic kidney disease], and perhaps cognitive function, physical function, sarcopenia, and quality of life?”
Dr. Pratley called for the development of a personalized approach to diabetes management that takes into account heterogeneity in disease pathogenesis, comorbidities, and patient preference.
“We need to change the focus to patient-important outcomes: dying, heart attack, strokes, and avoid therapeutic nihilism, which is still pervasive among many practitioners,” he said. “We also need to partner with primary care, because they take care of the majority of older individuals, and they need to understand how we’re evolving the goals of therapy. We need to educate them about the new guidelines and try to get them on board with some of the latest data that will help improve outcomes in our patients. We also need to understand the cost of diabetes and the cost effectiveness of interventions.”
He also recommends the development of a comprehensive evidence base for the use of drugs in older individuals. “I suggest pooled analyses within clinical development programs,” he said. “That’s been done for most development programs, but the phase 3 studies tend to enroll younger, healthier individuals. It would be good to do a meta-analysis across CVOTs [cardiovascular outcome trials] within different classes of medications.”
Dr. Pratley disclosed that all honoraria and fees he receives are directed to AdventHealth. These include serving on the advisory board or as consultant to AstraZeneca, GlaxoSmithKline, Glytec, Janssen, Ligand, Lilly, Merck, Mundipharma, Novo Nordisk, and Sanofi. He also has served as a speaker for AstraZeneca and Novo Nordisk, and has received research support from Lexicon, Ligand, Lilly, Merck, Novo Nordisk, and Sanofi. He receives no direct or indirect compensation.
LOS ANGELES – In the opinion of Richard Pratley, MD, it’s time for diabetes treatment guidelines to evolve in light of accumulating data from cardiovascular outcome trials in type 2 diabetes.
“They have evolved for the general patient population, and this should apply to older individuals as well,” Dr. Pratley said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “My fear is, there is therapeutic nihilism, the idea that by the time someone is 75 years old, the horse is out of the barn and you’re not going to be able to impact outcomes with directed therapy. I don’t think that’s true. Our current treatment guidelines for the treatment of diabetes in older individuals remain focused on glycemic control. It’s not hyperglycemia that’s killing people; it’s heart disease and renal disease.”
According to data from the United Nations, about 12% of the global population is older than 60. By 2050, that number is expected to reach 20%, which will continue to drive an epidemic of diabetes in the near future. Dr. Pratley, medical director of AdventHealth Diabetes Institute in Orlando, pointed out that diabetes in older individuals is not a homogeneous condition. “There are many people in my clinic who had type 1 diabetes diagnosed as kids, but I also have patients who have adult-onset type 1 diabetes,” he said. “We also have type 2 patients who can be diagnosed in their 20s, 30s, or 40s, and there are people who are diagnosed in their 70s and 80s. Now we are learning that there are different subtypes of diabetes; so even type 2 diabetes is not a homogeneous condition. There are people who are more insulin resistant or have more of an insulin secretory defect, and there’s a special type of older-onset type 2 diabetes. When you consider all this in talking about diabetes treatments, about 30% of patients in the United States are diagnosed [when they are] over the age of 60, so this is an ongoing issue.”
Older adults with diabetes may have longstanding diabetes with associated microvascular and macrovascular complications, he continued, or they may have newly diagnosed diabetes with evidence of end organ complications at the time of presentation. Or, they may have newly diagnosed diabetes without evidence of complications. “Does this matter? It does,” Dr. Pratley said. “The things we worry about with all patients with diabetes are the microvascular complications, but I would argue that the macrovascular complications, particularly diabetic nephropathy, are things we should have a laser focus on, because they have high morbidity and mortality, especially in older individuals.”
There are more than 28 cardiovascular outcomes trials in patients with type 2 diabetes ongoing or completed, and involving eight classes of medications, with more than 200,000 planned participants, Dr. Pratley said. Of those participants, 90,000 are older than 65 years, and 30,000 are older than 75 years. “This is great,” he said. “Not only do these cardiovascular outcome studies give us a lot of information about the safety and efficacy of these drugs in the general population, we can now dig in to this specific patient population.” For example, in cardiovascular outcomes trials with dipeptidyl peptidase–4 (DPP-4) inhibitors, the mean age of patients was 65. About half of the patients were older than 65, and 10%-14% were older than 75.
Investigators in the SAVOR-TIMI 53 trial examined age in one of their subgroup analyses (Diabetes Care. 2015;38:1145-53). In that study with saxagliptin, among people older than 65 who received the study drug, the hazard ratio for major adverse cardiac events (MACE) was 0.92, compared with 1.15 for those younger than 65 (P value for interaction = .058). “So older people did great [on this drug],” Dr. Pratley said. “In fact, they had a bit of a decreased risk.” A similar association was seen in adults aged 75 years and older (HR, 1.01 in those younger than 75 years, vs. 0.95 in those aged 75 years and older; P value for interaction = .673). “This is telling us that saxagliptin is safe in the older population.”
In the EXAMINE trial, in which patients with type 2 diabetes who had had a recent acute coronary syndrome received either alogliptin or placebo, researchers conducted an analysis of patients older and younger than 65 (N Engl J Med. 2013;369:1327-35). They observed no significant interactions on the primary composite cardiovascular outcome in those younger than 65 (HR, 0.91) and those aged 65 and older (HR, 0.98).
Dr. Pratley noted that in cardiovascular outcome trials with sodium-glucose transporter 2 (SGLT2) inhibitors, the mean age of patients was 64, and 48%-50% of them were older than 65. In the EMPA-REG OUTCOME trial of empagliflozin, the hazard ratio for the primary cardiovascular outcome was 1.04 in patients younger than 65 and 0.71 in those aged 65 and older (P = .01; N Engl J Med, 2015;373:2117-28). “That was a significant interaction,” he said. In addition, the hazard ratio for cardiovascular death was 0.72 in those younger than 65, and 0.54 in those aged 65 and older (P = .21). “There was not a significant interaction here, but clearly there was some trending in the older patient population,” Dr. Pratley said.
In the LEADER study of liraglutide in patients with diabetes, the hazard ratio for the primary composite cardiovascular outcome was 0.87 in the overall population, 0.78 in patients younger than 60, and 0.90 in those aged 60 and older (P = 0.27; N Engl J Med. 2016;375:311-22). In a post hoc analysis that stratified LEADER patients into younger than 75 and 75 and older, the researchers observed a 31% reduction in the 75 and older population, compared with a 10% reduction in the younger population (P for interaction = .09; Ann Intern Med. 2019;170[6]:423-6). “This was driven largely by a decrease in nonfatal [myocardial infarction],” said Dr. Pratley, who was one of the study investigators. “But in patients who were 75 years and older, there was a 30% reduction in all-cause mortality in those treated with liraglutide, compared with 12% in those younger than 75 (P for interaction = .22). That interaction is not significant, but the theme here is that older populations do quite well.”
Based on such evidence, he said, In particular, SGLT2 inhibitors and certain GLP-1 receptor agonists may be associated with an additional benefit in older individuals with cardiovascular disease, “perhaps because they’re the ones at highest risk,” Dr. Pratley said. “But we need further studies to better identify those older individuals who may be at highest risk of adverse cardiovascular complications from diabetes and who might benefit from targeted therapies.”
Many questions remain unanswered in efforts to provide optimal care to older adults with diabetes. “One of the problems is being inclusive in the older patient population,” Dr. Pratley said. “We tried to do a study of frail older individuals looking at different treatments and policies. It was difficult to recruit frail older individuals, even though they routinely are treated with the drugs we study in healthier populations. We need to know how to enroll patients, and which investigators are going to do these trials. Who is going to support these trials? Pharma? The NIH?”
Then there’s the question of what appropriate outcomes are in older individuals. “I think we can agree that hemoglobin A1c is a surrogate of microvascular complications,” he said. “Do we need to be looking at outcomes like MACE, hospitalization for heart failure, death, progression of [chronic kidney disease], and perhaps cognitive function, physical function, sarcopenia, and quality of life?”
Dr. Pratley called for the development of a personalized approach to diabetes management that takes into account heterogeneity in disease pathogenesis, comorbidities, and patient preference.
“We need to change the focus to patient-important outcomes: dying, heart attack, strokes, and avoid therapeutic nihilism, which is still pervasive among many practitioners,” he said. “We also need to partner with primary care, because they take care of the majority of older individuals, and they need to understand how we’re evolving the goals of therapy. We need to educate them about the new guidelines and try to get them on board with some of the latest data that will help improve outcomes in our patients. We also need to understand the cost of diabetes and the cost effectiveness of interventions.”
He also recommends the development of a comprehensive evidence base for the use of drugs in older individuals. “I suggest pooled analyses within clinical development programs,” he said. “That’s been done for most development programs, but the phase 3 studies tend to enroll younger, healthier individuals. It would be good to do a meta-analysis across CVOTs [cardiovascular outcome trials] within different classes of medications.”
Dr. Pratley disclosed that all honoraria and fees he receives are directed to AdventHealth. These include serving on the advisory board or as consultant to AstraZeneca, GlaxoSmithKline, Glytec, Janssen, Ligand, Lilly, Merck, Mundipharma, Novo Nordisk, and Sanofi. He also has served as a speaker for AstraZeneca and Novo Nordisk, and has received research support from Lexicon, Ligand, Lilly, Merck, Novo Nordisk, and Sanofi. He receives no direct or indirect compensation.
LOS ANGELES – In the opinion of Richard Pratley, MD, it’s time for diabetes treatment guidelines to evolve in light of accumulating data from cardiovascular outcome trials in type 2 diabetes.
“They have evolved for the general patient population, and this should apply to older individuals as well,” Dr. Pratley said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “My fear is, there is therapeutic nihilism, the idea that by the time someone is 75 years old, the horse is out of the barn and you’re not going to be able to impact outcomes with directed therapy. I don’t think that’s true. Our current treatment guidelines for the treatment of diabetes in older individuals remain focused on glycemic control. It’s not hyperglycemia that’s killing people; it’s heart disease and renal disease.”
According to data from the United Nations, about 12% of the global population is older than 60. By 2050, that number is expected to reach 20%, which will continue to drive an epidemic of diabetes in the near future. Dr. Pratley, medical director of AdventHealth Diabetes Institute in Orlando, pointed out that diabetes in older individuals is not a homogeneous condition. “There are many people in my clinic who had type 1 diabetes diagnosed as kids, but I also have patients who have adult-onset type 1 diabetes,” he said. “We also have type 2 patients who can be diagnosed in their 20s, 30s, or 40s, and there are people who are diagnosed in their 70s and 80s. Now we are learning that there are different subtypes of diabetes; so even type 2 diabetes is not a homogeneous condition. There are people who are more insulin resistant or have more of an insulin secretory defect, and there’s a special type of older-onset type 2 diabetes. When you consider all this in talking about diabetes treatments, about 30% of patients in the United States are diagnosed [when they are] over the age of 60, so this is an ongoing issue.”
Older adults with diabetes may have longstanding diabetes with associated microvascular and macrovascular complications, he continued, or they may have newly diagnosed diabetes with evidence of end organ complications at the time of presentation. Or, they may have newly diagnosed diabetes without evidence of complications. “Does this matter? It does,” Dr. Pratley said. “The things we worry about with all patients with diabetes are the microvascular complications, but I would argue that the macrovascular complications, particularly diabetic nephropathy, are things we should have a laser focus on, because they have high morbidity and mortality, especially in older individuals.”
There are more than 28 cardiovascular outcomes trials in patients with type 2 diabetes ongoing or completed, and involving eight classes of medications, with more than 200,000 planned participants, Dr. Pratley said. Of those participants, 90,000 are older than 65 years, and 30,000 are older than 75 years. “This is great,” he said. “Not only do these cardiovascular outcome studies give us a lot of information about the safety and efficacy of these drugs in the general population, we can now dig in to this specific patient population.” For example, in cardiovascular outcomes trials with dipeptidyl peptidase–4 (DPP-4) inhibitors, the mean age of patients was 65. About half of the patients were older than 65, and 10%-14% were older than 75.
Investigators in the SAVOR-TIMI 53 trial examined age in one of their subgroup analyses (Diabetes Care. 2015;38:1145-53). In that study with saxagliptin, among people older than 65 who received the study drug, the hazard ratio for major adverse cardiac events (MACE) was 0.92, compared with 1.15 for those younger than 65 (P value for interaction = .058). “So older people did great [on this drug],” Dr. Pratley said. “In fact, they had a bit of a decreased risk.” A similar association was seen in adults aged 75 years and older (HR, 1.01 in those younger than 75 years, vs. 0.95 in those aged 75 years and older; P value for interaction = .673). “This is telling us that saxagliptin is safe in the older population.”
In the EXAMINE trial, in which patients with type 2 diabetes who had had a recent acute coronary syndrome received either alogliptin or placebo, researchers conducted an analysis of patients older and younger than 65 (N Engl J Med. 2013;369:1327-35). They observed no significant interactions on the primary composite cardiovascular outcome in those younger than 65 (HR, 0.91) and those aged 65 and older (HR, 0.98).
Dr. Pratley noted that in cardiovascular outcome trials with sodium-glucose transporter 2 (SGLT2) inhibitors, the mean age of patients was 64, and 48%-50% of them were older than 65. In the EMPA-REG OUTCOME trial of empagliflozin, the hazard ratio for the primary cardiovascular outcome was 1.04 in patients younger than 65 and 0.71 in those aged 65 and older (P = .01; N Engl J Med, 2015;373:2117-28). “That was a significant interaction,” he said. In addition, the hazard ratio for cardiovascular death was 0.72 in those younger than 65, and 0.54 in those aged 65 and older (P = .21). “There was not a significant interaction here, but clearly there was some trending in the older patient population,” Dr. Pratley said.
In the LEADER study of liraglutide in patients with diabetes, the hazard ratio for the primary composite cardiovascular outcome was 0.87 in the overall population, 0.78 in patients younger than 60, and 0.90 in those aged 60 and older (P = 0.27; N Engl J Med. 2016;375:311-22). In a post hoc analysis that stratified LEADER patients into younger than 75 and 75 and older, the researchers observed a 31% reduction in the 75 and older population, compared with a 10% reduction in the younger population (P for interaction = .09; Ann Intern Med. 2019;170[6]:423-6). “This was driven largely by a decrease in nonfatal [myocardial infarction],” said Dr. Pratley, who was one of the study investigators. “But in patients who were 75 years and older, there was a 30% reduction in all-cause mortality in those treated with liraglutide, compared with 12% in those younger than 75 (P for interaction = .22). That interaction is not significant, but the theme here is that older populations do quite well.”
Based on such evidence, he said, In particular, SGLT2 inhibitors and certain GLP-1 receptor agonists may be associated with an additional benefit in older individuals with cardiovascular disease, “perhaps because they’re the ones at highest risk,” Dr. Pratley said. “But we need further studies to better identify those older individuals who may be at highest risk of adverse cardiovascular complications from diabetes and who might benefit from targeted therapies.”
Many questions remain unanswered in efforts to provide optimal care to older adults with diabetes. “One of the problems is being inclusive in the older patient population,” Dr. Pratley said. “We tried to do a study of frail older individuals looking at different treatments and policies. It was difficult to recruit frail older individuals, even though they routinely are treated with the drugs we study in healthier populations. We need to know how to enroll patients, and which investigators are going to do these trials. Who is going to support these trials? Pharma? The NIH?”
Then there’s the question of what appropriate outcomes are in older individuals. “I think we can agree that hemoglobin A1c is a surrogate of microvascular complications,” he said. “Do we need to be looking at outcomes like MACE, hospitalization for heart failure, death, progression of [chronic kidney disease], and perhaps cognitive function, physical function, sarcopenia, and quality of life?”
Dr. Pratley called for the development of a personalized approach to diabetes management that takes into account heterogeneity in disease pathogenesis, comorbidities, and patient preference.
“We need to change the focus to patient-important outcomes: dying, heart attack, strokes, and avoid therapeutic nihilism, which is still pervasive among many practitioners,” he said. “We also need to partner with primary care, because they take care of the majority of older individuals, and they need to understand how we’re evolving the goals of therapy. We need to educate them about the new guidelines and try to get them on board with some of the latest data that will help improve outcomes in our patients. We also need to understand the cost of diabetes and the cost effectiveness of interventions.”
He also recommends the development of a comprehensive evidence base for the use of drugs in older individuals. “I suggest pooled analyses within clinical development programs,” he said. “That’s been done for most development programs, but the phase 3 studies tend to enroll younger, healthier individuals. It would be good to do a meta-analysis across CVOTs [cardiovascular outcome trials] within different classes of medications.”
Dr. Pratley disclosed that all honoraria and fees he receives are directed to AdventHealth. These include serving on the advisory board or as consultant to AstraZeneca, GlaxoSmithKline, Glytec, Janssen, Ligand, Lilly, Merck, Mundipharma, Novo Nordisk, and Sanofi. He also has served as a speaker for AstraZeneca and Novo Nordisk, and has received research support from Lexicon, Ligand, Lilly, Merck, Novo Nordisk, and Sanofi. He receives no direct or indirect compensation.
EXPERT ANALYSIS FROM WCIRDC 2019
ENGAGE AF-TIMI: Insulin linked to greater risk for stroke, CV death, bleeding
LOS ANGELES – Patients with diabetes had significantly higher adjusted risk of bleeding, cardiovascular-related death, and poorer net outcomes, particularly those treated with insulin, a subanalysis of the ENGAGE AF-TIMI 48 trial has shown.
In addition, the pharmacokinetic and pharmacodynamic profile of the study drug, edoxaban – a novel oral anticoagulant drug and a direct factor Xa inhibitor – was generally similar in patients with and without diabetes.
“We know that atrial fibrillation is associated with a fivefold increased risk of stroke,” Anna Plitt, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Type 2 diabetes is associated with a twofold increased risk of stroke, and longer duration of diabetes is associated with even higher ischemic event rates. The coexistence of [atrial fibrillation] and type 2 diabetes further increases thromboembolic risk.”
Dr. Plitt, a cardiology fellow at Mount Sinai Hospital, New York, noted that, although type 2 diabetes is characterized by a prothrombotic and inflammatory state, the mechanism of action by which hyperglycemia and/or insulin resistance leads to the development of atrial fibrillation (AFib) remains unknown. “Given the complex clinical interactions between AFib and type 2 diabetes, care for these patients remains challenging,” she said. “Recommendations for anticoagulation managements vary based on the presence of additional risk factors and which guidelines are followed.”
In the ENGAGE AF-TIMI 48 trial, 21,105 patients with documented AFib within the previous 12 months were randomized to standard-care warfarin or high-dose edoxaban (60 mg daily) or low-dose edoxaban (30 mg daily). The edoxaban dose was reduced by 50% if creatinine clearance reached 30-50 mL/min, patient weight reached 60 kg or less, or there was concomitant use of a P-glycoprotein inhibitor (N Engl J Med. 2013;369:2093-104). The median follow-up was 2.8 years, and the primary efficacy endpoint was stroke or systemic embolic events (SEEs). The primary safety endpoint was major bleeding, as defined by the International Society on Thrombosis and Haemostasis criteria.
The findings showed that edoxaban was noninferior to warfarin in preventing stroke/SEEs. It also significantly reduced major bleeding, cardiovascular death, and net outcomes. “Therefore, the higher dose of edoxaban was approved globally for treating patients with AFib,” Dr. Plitt said. “The lower-dose regimen was not approved because there was less protection from ischemic stroke, compared with warfarin.”
For the current subanalysis, Dr. Plitt and colleagues set out to further evaluate outcomes of patients enrolled in the ENGAGE AF-TIMI 48 trial, excluding those who were in the low-dose edoxaban group. The presence or absence of diabetes was determined by the local investigator at randomization. The investigators further stratified patients into insulin-treated and non–insulin treated groups and used multivariate Cox regression models to adjust for baseline characteristics across the groups stratified by diabetes status. Next, they analyzed edoxaban concentration, anti–factor Xa activity, and international normalized ratio data and compared outcomes of high-dose edoxaban with those of warfarin.
The primary endpoint and the primary safety endpoint of interest were the same as in the main ENGAGE AF-TIMI 48 trial. Key secondary endpoints included in the subanalysis were cardiovascular death, stroke/SEE, major adverse cardiovascular events (MACE, a composite of myocardial infarction, stroke, SEE, or death because of cardiovascular cause or bleeding), and all-cause death.
In all, 7,624 of the 21,105 patients in the ENGAGE AF-TIMI 48 trial had diabetes, for a rate of 36%. Most of the patients with diabetes did not require insulin (30%), while 6% did. There were fewer female patients with diabetes than without (37% vs. 39%, respectively). Of note was that history of prior stroke/transient ischemic attack was higher in the no-diabetes group than in the diabetes group (33% vs. 21%), as was congestive heart failure (63% vs. 48%).
The mean CHA2DS2-VASc score for predicting thromboembolic risk (0, low risk; greater than 1, high risk) was 4.6 in the diabetes group and 4.2 in the no-diabetes group. When diabetes was not included in the score, the mean CHA2DS2-VASc score was 3.6 in the diabetes group. “Because the trial entry criteria required a minimum CHADS2 score of 2, patients without diabetes were enriched with stroke risk factors other than diabetes,” Dr. Plitt said.
Adjusted outcomes from the subanalysis showed that the risk of stroke/SEE was similar between patients with and without diabetes (hazard ratio, 1.08). However, patients with diabetes were at higher adjusted risk for cardiovascular death than patients without diabetes (HR, 1.29), MACE (HR, 1.28), major bleed (HR, 1.28), and the net outcome of stroke, SEE, major bleed, or all-cause death (HR, 1.25).
The researchers also analyzed the pharmacodynamic and pharmacokinetic data of high-dose edoxaban, stratified by diabetes status. They found that the parameters were generally similar between patients with and without diabetes, including trough concentrations of edoxaban (34.3 and 37.2 ng/mL, respectively; P = .04), trough exogenous anti–factor Xa activity (0.59 and 0.68 IU/mL; P = .11), and the percentage change from baseline in the peak endogenous anti–factor Xa activity (P = .66). The percentage changes from baseline of the trough endogenous anti–factor Xa activity was slightly lower in patients with diabetes, compared with patients without diabetes (P less than .001). “However, these modest differences between the two groups are of unclear clinical significance,” Dr. Plitt said.
Results from the main ENGAGE AF-TIMI 48 showed that the rates of stroke/SEE were reduced by 13% on high-dose edoxaban. However, the subanalysis found no significant effect modification in the reduction in stroke/SEE with edoxaban, compared with warfarin, when stratified by diabetes status (reductions of 16% vs. 7% in the no-diabetes and diabetes groups, respectively; P for interaction = .54). The researchers also observed similar reductions with edoxaban in the risks of secondary outcomes when patients were stratified by diabetes status.
In another finding, patients with diabetes who were treated with insulin were at a higher adjusted risk for all outcomes, compared with those with diabetes who were not treated with insulin. This included stroke/SEE (HR, 1.44), cardiovascular-related death (HR, 1.83), MACE (HR, 1.78), major bleed (HR, 1.31), and net outcome (HR, 1.57).
Next, the researchers compared the study endpoints of high-dose edoxaban and warfarin, with and without insulin. “None of the efficacy, safety, or net outcomes demonstrated evidence of treatment effect modification related to the use of insulin among [patients with diabetes],” she said.
Dr. Plitt disclosed having received honoraria for educational activities from Bristol-Myers Squibb.
LOS ANGELES – Patients with diabetes had significantly higher adjusted risk of bleeding, cardiovascular-related death, and poorer net outcomes, particularly those treated with insulin, a subanalysis of the ENGAGE AF-TIMI 48 trial has shown.
In addition, the pharmacokinetic and pharmacodynamic profile of the study drug, edoxaban – a novel oral anticoagulant drug and a direct factor Xa inhibitor – was generally similar in patients with and without diabetes.
“We know that atrial fibrillation is associated with a fivefold increased risk of stroke,” Anna Plitt, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Type 2 diabetes is associated with a twofold increased risk of stroke, and longer duration of diabetes is associated with even higher ischemic event rates. The coexistence of [atrial fibrillation] and type 2 diabetes further increases thromboembolic risk.”
Dr. Plitt, a cardiology fellow at Mount Sinai Hospital, New York, noted that, although type 2 diabetes is characterized by a prothrombotic and inflammatory state, the mechanism of action by which hyperglycemia and/or insulin resistance leads to the development of atrial fibrillation (AFib) remains unknown. “Given the complex clinical interactions between AFib and type 2 diabetes, care for these patients remains challenging,” she said. “Recommendations for anticoagulation managements vary based on the presence of additional risk factors and which guidelines are followed.”
In the ENGAGE AF-TIMI 48 trial, 21,105 patients with documented AFib within the previous 12 months were randomized to standard-care warfarin or high-dose edoxaban (60 mg daily) or low-dose edoxaban (30 mg daily). The edoxaban dose was reduced by 50% if creatinine clearance reached 30-50 mL/min, patient weight reached 60 kg or less, or there was concomitant use of a P-glycoprotein inhibitor (N Engl J Med. 2013;369:2093-104). The median follow-up was 2.8 years, and the primary efficacy endpoint was stroke or systemic embolic events (SEEs). The primary safety endpoint was major bleeding, as defined by the International Society on Thrombosis and Haemostasis criteria.
The findings showed that edoxaban was noninferior to warfarin in preventing stroke/SEEs. It also significantly reduced major bleeding, cardiovascular death, and net outcomes. “Therefore, the higher dose of edoxaban was approved globally for treating patients with AFib,” Dr. Plitt said. “The lower-dose regimen was not approved because there was less protection from ischemic stroke, compared with warfarin.”
For the current subanalysis, Dr. Plitt and colleagues set out to further evaluate outcomes of patients enrolled in the ENGAGE AF-TIMI 48 trial, excluding those who were in the low-dose edoxaban group. The presence or absence of diabetes was determined by the local investigator at randomization. The investigators further stratified patients into insulin-treated and non–insulin treated groups and used multivariate Cox regression models to adjust for baseline characteristics across the groups stratified by diabetes status. Next, they analyzed edoxaban concentration, anti–factor Xa activity, and international normalized ratio data and compared outcomes of high-dose edoxaban with those of warfarin.
The primary endpoint and the primary safety endpoint of interest were the same as in the main ENGAGE AF-TIMI 48 trial. Key secondary endpoints included in the subanalysis were cardiovascular death, stroke/SEE, major adverse cardiovascular events (MACE, a composite of myocardial infarction, stroke, SEE, or death because of cardiovascular cause or bleeding), and all-cause death.
In all, 7,624 of the 21,105 patients in the ENGAGE AF-TIMI 48 trial had diabetes, for a rate of 36%. Most of the patients with diabetes did not require insulin (30%), while 6% did. There were fewer female patients with diabetes than without (37% vs. 39%, respectively). Of note was that history of prior stroke/transient ischemic attack was higher in the no-diabetes group than in the diabetes group (33% vs. 21%), as was congestive heart failure (63% vs. 48%).
The mean CHA2DS2-VASc score for predicting thromboembolic risk (0, low risk; greater than 1, high risk) was 4.6 in the diabetes group and 4.2 in the no-diabetes group. When diabetes was not included in the score, the mean CHA2DS2-VASc score was 3.6 in the diabetes group. “Because the trial entry criteria required a minimum CHADS2 score of 2, patients without diabetes were enriched with stroke risk factors other than diabetes,” Dr. Plitt said.
Adjusted outcomes from the subanalysis showed that the risk of stroke/SEE was similar between patients with and without diabetes (hazard ratio, 1.08). However, patients with diabetes were at higher adjusted risk for cardiovascular death than patients without diabetes (HR, 1.29), MACE (HR, 1.28), major bleed (HR, 1.28), and the net outcome of stroke, SEE, major bleed, or all-cause death (HR, 1.25).
The researchers also analyzed the pharmacodynamic and pharmacokinetic data of high-dose edoxaban, stratified by diabetes status. They found that the parameters were generally similar between patients with and without diabetes, including trough concentrations of edoxaban (34.3 and 37.2 ng/mL, respectively; P = .04), trough exogenous anti–factor Xa activity (0.59 and 0.68 IU/mL; P = .11), and the percentage change from baseline in the peak endogenous anti–factor Xa activity (P = .66). The percentage changes from baseline of the trough endogenous anti–factor Xa activity was slightly lower in patients with diabetes, compared with patients without diabetes (P less than .001). “However, these modest differences between the two groups are of unclear clinical significance,” Dr. Plitt said.
Results from the main ENGAGE AF-TIMI 48 showed that the rates of stroke/SEE were reduced by 13% on high-dose edoxaban. However, the subanalysis found no significant effect modification in the reduction in stroke/SEE with edoxaban, compared with warfarin, when stratified by diabetes status (reductions of 16% vs. 7% in the no-diabetes and diabetes groups, respectively; P for interaction = .54). The researchers also observed similar reductions with edoxaban in the risks of secondary outcomes when patients were stratified by diabetes status.
In another finding, patients with diabetes who were treated with insulin were at a higher adjusted risk for all outcomes, compared with those with diabetes who were not treated with insulin. This included stroke/SEE (HR, 1.44), cardiovascular-related death (HR, 1.83), MACE (HR, 1.78), major bleed (HR, 1.31), and net outcome (HR, 1.57).
Next, the researchers compared the study endpoints of high-dose edoxaban and warfarin, with and without insulin. “None of the efficacy, safety, or net outcomes demonstrated evidence of treatment effect modification related to the use of insulin among [patients with diabetes],” she said.
Dr. Plitt disclosed having received honoraria for educational activities from Bristol-Myers Squibb.
LOS ANGELES – Patients with diabetes had significantly higher adjusted risk of bleeding, cardiovascular-related death, and poorer net outcomes, particularly those treated with insulin, a subanalysis of the ENGAGE AF-TIMI 48 trial has shown.
In addition, the pharmacokinetic and pharmacodynamic profile of the study drug, edoxaban – a novel oral anticoagulant drug and a direct factor Xa inhibitor – was generally similar in patients with and without diabetes.
“We know that atrial fibrillation is associated with a fivefold increased risk of stroke,” Anna Plitt, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Type 2 diabetes is associated with a twofold increased risk of stroke, and longer duration of diabetes is associated with even higher ischemic event rates. The coexistence of [atrial fibrillation] and type 2 diabetes further increases thromboembolic risk.”
Dr. Plitt, a cardiology fellow at Mount Sinai Hospital, New York, noted that, although type 2 diabetes is characterized by a prothrombotic and inflammatory state, the mechanism of action by which hyperglycemia and/or insulin resistance leads to the development of atrial fibrillation (AFib) remains unknown. “Given the complex clinical interactions between AFib and type 2 diabetes, care for these patients remains challenging,” she said. “Recommendations for anticoagulation managements vary based on the presence of additional risk factors and which guidelines are followed.”
In the ENGAGE AF-TIMI 48 trial, 21,105 patients with documented AFib within the previous 12 months were randomized to standard-care warfarin or high-dose edoxaban (60 mg daily) or low-dose edoxaban (30 mg daily). The edoxaban dose was reduced by 50% if creatinine clearance reached 30-50 mL/min, patient weight reached 60 kg or less, or there was concomitant use of a P-glycoprotein inhibitor (N Engl J Med. 2013;369:2093-104). The median follow-up was 2.8 years, and the primary efficacy endpoint was stroke or systemic embolic events (SEEs). The primary safety endpoint was major bleeding, as defined by the International Society on Thrombosis and Haemostasis criteria.
The findings showed that edoxaban was noninferior to warfarin in preventing stroke/SEEs. It also significantly reduced major bleeding, cardiovascular death, and net outcomes. “Therefore, the higher dose of edoxaban was approved globally for treating patients with AFib,” Dr. Plitt said. “The lower-dose regimen was not approved because there was less protection from ischemic stroke, compared with warfarin.”
For the current subanalysis, Dr. Plitt and colleagues set out to further evaluate outcomes of patients enrolled in the ENGAGE AF-TIMI 48 trial, excluding those who were in the low-dose edoxaban group. The presence or absence of diabetes was determined by the local investigator at randomization. The investigators further stratified patients into insulin-treated and non–insulin treated groups and used multivariate Cox regression models to adjust for baseline characteristics across the groups stratified by diabetes status. Next, they analyzed edoxaban concentration, anti–factor Xa activity, and international normalized ratio data and compared outcomes of high-dose edoxaban with those of warfarin.
The primary endpoint and the primary safety endpoint of interest were the same as in the main ENGAGE AF-TIMI 48 trial. Key secondary endpoints included in the subanalysis were cardiovascular death, stroke/SEE, major adverse cardiovascular events (MACE, a composite of myocardial infarction, stroke, SEE, or death because of cardiovascular cause or bleeding), and all-cause death.
In all, 7,624 of the 21,105 patients in the ENGAGE AF-TIMI 48 trial had diabetes, for a rate of 36%. Most of the patients with diabetes did not require insulin (30%), while 6% did. There were fewer female patients with diabetes than without (37% vs. 39%, respectively). Of note was that history of prior stroke/transient ischemic attack was higher in the no-diabetes group than in the diabetes group (33% vs. 21%), as was congestive heart failure (63% vs. 48%).
The mean CHA2DS2-VASc score for predicting thromboembolic risk (0, low risk; greater than 1, high risk) was 4.6 in the diabetes group and 4.2 in the no-diabetes group. When diabetes was not included in the score, the mean CHA2DS2-VASc score was 3.6 in the diabetes group. “Because the trial entry criteria required a minimum CHADS2 score of 2, patients without diabetes were enriched with stroke risk factors other than diabetes,” Dr. Plitt said.
Adjusted outcomes from the subanalysis showed that the risk of stroke/SEE was similar between patients with and without diabetes (hazard ratio, 1.08). However, patients with diabetes were at higher adjusted risk for cardiovascular death than patients without diabetes (HR, 1.29), MACE (HR, 1.28), major bleed (HR, 1.28), and the net outcome of stroke, SEE, major bleed, or all-cause death (HR, 1.25).
The researchers also analyzed the pharmacodynamic and pharmacokinetic data of high-dose edoxaban, stratified by diabetes status. They found that the parameters were generally similar between patients with and without diabetes, including trough concentrations of edoxaban (34.3 and 37.2 ng/mL, respectively; P = .04), trough exogenous anti–factor Xa activity (0.59 and 0.68 IU/mL; P = .11), and the percentage change from baseline in the peak endogenous anti–factor Xa activity (P = .66). The percentage changes from baseline of the trough endogenous anti–factor Xa activity was slightly lower in patients with diabetes, compared with patients without diabetes (P less than .001). “However, these modest differences between the two groups are of unclear clinical significance,” Dr. Plitt said.
Results from the main ENGAGE AF-TIMI 48 showed that the rates of stroke/SEE were reduced by 13% on high-dose edoxaban. However, the subanalysis found no significant effect modification in the reduction in stroke/SEE with edoxaban, compared with warfarin, when stratified by diabetes status (reductions of 16% vs. 7% in the no-diabetes and diabetes groups, respectively; P for interaction = .54). The researchers also observed similar reductions with edoxaban in the risks of secondary outcomes when patients were stratified by diabetes status.
In another finding, patients with diabetes who were treated with insulin were at a higher adjusted risk for all outcomes, compared with those with diabetes who were not treated with insulin. This included stroke/SEE (HR, 1.44), cardiovascular-related death (HR, 1.83), MACE (HR, 1.78), major bleed (HR, 1.31), and net outcome (HR, 1.57).
Next, the researchers compared the study endpoints of high-dose edoxaban and warfarin, with and without insulin. “None of the efficacy, safety, or net outcomes demonstrated evidence of treatment effect modification related to the use of insulin among [patients with diabetes],” she said.
Dr. Plitt disclosed having received honoraria for educational activities from Bristol-Myers Squibb.
REPORTING FROM THE WCIRDC 2019
FDA authorizes customizable automated glycemic controller
The Food and Drug Administration has authorized marketing of the Tandem Diabetes Care Control-IQ Technology, an interoperable automated glycemic controller, for use in a customizable glucose control system, according to a release from the agency.
The move also paves the way for the review and authorization of similar devices in the future.
The Control-IQ Technology controller coordinates with an alternate controller-enabled insulin pump and an integrated continuous glucose monitor, which can be made by other manufacturers as long they are compatible with this modular technology.
The agency reviewed data from a clinical study of 168 patients with type 1 diabetes who were randomized to use either the Control-IQ Technology controller installed on a Tandem t:slim X2 insulin pump, or a continuous glucose monitor and insulin pump without the Control-IQ controller. The findings showed that,
However, the agency noted that, although the system has been assessed for reliability, delays in insulin delivery remain possible and care should be taken when using it.
This authorization comes along with establishment of criteria and regulatory requirements that create a new regulatory classification for this type of device, whereby future devices of the same type and with the same purpose can go through the FDA’s 510(k) premarket process. Such a process would mean that, going forward, similar devices can “obtain marketing authorization by demonstrating substantial equivalence to a predicate device.”
More information can be found in the full release, available on the FDA website.
The Food and Drug Administration has authorized marketing of the Tandem Diabetes Care Control-IQ Technology, an interoperable automated glycemic controller, for use in a customizable glucose control system, according to a release from the agency.
The move also paves the way for the review and authorization of similar devices in the future.
The Control-IQ Technology controller coordinates with an alternate controller-enabled insulin pump and an integrated continuous glucose monitor, which can be made by other manufacturers as long they are compatible with this modular technology.
The agency reviewed data from a clinical study of 168 patients with type 1 diabetes who were randomized to use either the Control-IQ Technology controller installed on a Tandem t:slim X2 insulin pump, or a continuous glucose monitor and insulin pump without the Control-IQ controller. The findings showed that,
However, the agency noted that, although the system has been assessed for reliability, delays in insulin delivery remain possible and care should be taken when using it.
This authorization comes along with establishment of criteria and regulatory requirements that create a new regulatory classification for this type of device, whereby future devices of the same type and with the same purpose can go through the FDA’s 510(k) premarket process. Such a process would mean that, going forward, similar devices can “obtain marketing authorization by demonstrating substantial equivalence to a predicate device.”
More information can be found in the full release, available on the FDA website.
The Food and Drug Administration has authorized marketing of the Tandem Diabetes Care Control-IQ Technology, an interoperable automated glycemic controller, for use in a customizable glucose control system, according to a release from the agency.
The move also paves the way for the review and authorization of similar devices in the future.
The Control-IQ Technology controller coordinates with an alternate controller-enabled insulin pump and an integrated continuous glucose monitor, which can be made by other manufacturers as long they are compatible with this modular technology.
The agency reviewed data from a clinical study of 168 patients with type 1 diabetes who were randomized to use either the Control-IQ Technology controller installed on a Tandem t:slim X2 insulin pump, or a continuous glucose monitor and insulin pump without the Control-IQ controller. The findings showed that,
However, the agency noted that, although the system has been assessed for reliability, delays in insulin delivery remain possible and care should be taken when using it.
This authorization comes along with establishment of criteria and regulatory requirements that create a new regulatory classification for this type of device, whereby future devices of the same type and with the same purpose can go through the FDA’s 510(k) premarket process. Such a process would mean that, going forward, similar devices can “obtain marketing authorization by demonstrating substantial equivalence to a predicate device.”
More information can be found in the full release, available on the FDA website.
Could liraglutide stall the onset of type 2 diabetes in children?
LOS ANGELES – Until the recent approval of liraglutide for the treatment of children and adolescents with type 2 diabetes, investigators like Sonia Caprio, MD, were at their wits’ end watching the beta-cell function of their patients decline on metformin treatment.
“The kids were not doing well. It was like they were being treated with water,” Dr. Caprio, a pediatric endocrinologist at Yale University, New Haven, Conn., said at the annual World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease.
For example, in the NIH-funded TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study that began enrollment in 2004, 699 patients aged between 10 and 17 years and with type 2 diabetes were treated with metformin (1,000 mg, twice daily) to attain a glycated hemoglobin level of less than 8% and were then randomly assigned to continued treatment with metformin alone or to metformin combined with rosiglitazone (4 mg, twice a day) or a lifestyle-intervention program that focused on weight loss through modifying eating and activity behaviors (N Engl J Med. 2012;366:2247-56).
Over the course of 11 months, the researchers found that 46% of the children were failing treatment. “The worst arm was the metformin arm,” said Dr. Caprio, who was involved with the study. “Kids were not responding to the drug at all. About 52% of children failed to do better using metformin – a classic drug that we all start kids on when we diagnose them with type 2 diabetes.”
Findings from a follow-up study, TODAY2, showed that these young patients were prone to serious diabetes-related events, such as heart attacks, chronic kidney disease, retinal disease, neuropathy, and complications in the offspring of pregnancies.
In addition, results from the RISE (Restoring Insulin Secretion) Pediatric Medication Study found that, in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes, neither 3 months of insulin glargine followed by 9 months of metformin nor 12 months of metformin alone halted the progressive deterioration of beta-cell function (Diabetes Care. 2018 Aug; 41[8]:1717-25).
“The uniqueness of RISE is that we employed very sophisticated techniques to measure insulin secretion and sensitivity while they were being treated with these usual drugs,” said Dr. Caprio, who was one of the study investigators. “The beta cell is unresponsive to metformin and other treatments. The question is, why?”
Despite these findings, 2018 consensus guidelines from the American Diabetes Association on the evaluation and management of youth-onset diabetes (Diabetes Care. 2018;41:2648-68) call for the administration of metformin twice daily in youth with new-onset diabetes who have a hemoglobin A1c (HbA1c) level of less than 8.5%. “I argue that is not the way. We need better ways to treat [these patients] because they are moving fast to having complications,” she said.
Enter the Ellipse Trial, a pivotal multicenter, randomized study that evaluated the effect of the glucagonlike peptide-1 receptor agonist liraglutide in children and adolescents with type 2 diabetes (N Engl J Med. 2019;381:637-46).
Researchers, led by William V. Tamborlane, MD, chief of Yale Medicine Pediatric Endocrinology, also in New Haven, randomized 135 patients to one of two arms: 66 to subcutaneous liraglutide (up to 1.8 mg/day) and 69 to placebo for a 26-week, double-blind period, followed by a 26-week open-label extension period. All patients received metformin during the trial. More than half of the study participants (62%) were female, the mean age was 15 years, 65% were white, the mean body mass index was 33.9 kg/m2, their mean fasting glucose was 8.4 mmol/L, and their mean HbA1c was 7.8%.
for an estimated treatment difference of −1.06 percentage points (P less than .001). By 52 weeks, the difference increased to −1.30 percentage points.
“There was also a significant drop in BMI z score in patients treated with liraglutide, which is important,” Dr. Caprio said. “This medication is having an impact on weight, which is a key driver of the onset of type 2 diabetes in youth. This is a remarkable achievement because weight loss is hard to achieve in obese adolescents, as we showed in the TODAY study.”
The number of adverse events reported by patients was similar in the treatment and placebo groups (85% and 81%, respectively), but the overall rates of adverse events and gastrointestinal adverse events were higher with liraglutide.
“I use liraglutide just for weight reduction because I mainly see a lot of kids with obesity. Many kids are not responding because of the GI effects of this drug. I think the weight loss could have been better had the investigators moved to a dose of 1.8 mg, which we use in adults.”
A fasting plasma glucose of 6.1 mmol/L was the primary reason for participants remaining on a lower dose of liraglutide, she said. At the same time, liraglutide concentration data indicated a high rate of noncompliance, which was expected in this population. “That’s a big problem we face with children,” Dr. Caprio said. “Some of them are not constantly taking the medication. They skip doses a lot. But that happens with patients in this age group.”
“Finally, we have something else to help children and teenagers to delay the complications we are seeing,” Dr. Caprio said. “To me, I think this is a new era. I have hope. It will be interesting to see whether liraglutide and perhaps SGLT2 [sodium-glucose transporter 2] inhibitors can delay the onset of type 2 diabetes in children. In my view, we will be doing this with drugs. I don’t think the weight loss [concerns are] going to go away without medication, unfortunately.”
Dr. Caprio reported having no financial disclosures.
LOS ANGELES – Until the recent approval of liraglutide for the treatment of children and adolescents with type 2 diabetes, investigators like Sonia Caprio, MD, were at their wits’ end watching the beta-cell function of their patients decline on metformin treatment.
“The kids were not doing well. It was like they were being treated with water,” Dr. Caprio, a pediatric endocrinologist at Yale University, New Haven, Conn., said at the annual World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease.
For example, in the NIH-funded TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study that began enrollment in 2004, 699 patients aged between 10 and 17 years and with type 2 diabetes were treated with metformin (1,000 mg, twice daily) to attain a glycated hemoglobin level of less than 8% and were then randomly assigned to continued treatment with metformin alone or to metformin combined with rosiglitazone (4 mg, twice a day) or a lifestyle-intervention program that focused on weight loss through modifying eating and activity behaviors (N Engl J Med. 2012;366:2247-56).
Over the course of 11 months, the researchers found that 46% of the children were failing treatment. “The worst arm was the metformin arm,” said Dr. Caprio, who was involved with the study. “Kids were not responding to the drug at all. About 52% of children failed to do better using metformin – a classic drug that we all start kids on when we diagnose them with type 2 diabetes.”
Findings from a follow-up study, TODAY2, showed that these young patients were prone to serious diabetes-related events, such as heart attacks, chronic kidney disease, retinal disease, neuropathy, and complications in the offspring of pregnancies.
In addition, results from the RISE (Restoring Insulin Secretion) Pediatric Medication Study found that, in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes, neither 3 months of insulin glargine followed by 9 months of metformin nor 12 months of metformin alone halted the progressive deterioration of beta-cell function (Diabetes Care. 2018 Aug; 41[8]:1717-25).
“The uniqueness of RISE is that we employed very sophisticated techniques to measure insulin secretion and sensitivity while they were being treated with these usual drugs,” said Dr. Caprio, who was one of the study investigators. “The beta cell is unresponsive to metformin and other treatments. The question is, why?”
Despite these findings, 2018 consensus guidelines from the American Diabetes Association on the evaluation and management of youth-onset diabetes (Diabetes Care. 2018;41:2648-68) call for the administration of metformin twice daily in youth with new-onset diabetes who have a hemoglobin A1c (HbA1c) level of less than 8.5%. “I argue that is not the way. We need better ways to treat [these patients] because they are moving fast to having complications,” she said.
Enter the Ellipse Trial, a pivotal multicenter, randomized study that evaluated the effect of the glucagonlike peptide-1 receptor agonist liraglutide in children and adolescents with type 2 diabetes (N Engl J Med. 2019;381:637-46).
Researchers, led by William V. Tamborlane, MD, chief of Yale Medicine Pediatric Endocrinology, also in New Haven, randomized 135 patients to one of two arms: 66 to subcutaneous liraglutide (up to 1.8 mg/day) and 69 to placebo for a 26-week, double-blind period, followed by a 26-week open-label extension period. All patients received metformin during the trial. More than half of the study participants (62%) were female, the mean age was 15 years, 65% were white, the mean body mass index was 33.9 kg/m2, their mean fasting glucose was 8.4 mmol/L, and their mean HbA1c was 7.8%.
for an estimated treatment difference of −1.06 percentage points (P less than .001). By 52 weeks, the difference increased to −1.30 percentage points.
“There was also a significant drop in BMI z score in patients treated with liraglutide, which is important,” Dr. Caprio said. “This medication is having an impact on weight, which is a key driver of the onset of type 2 diabetes in youth. This is a remarkable achievement because weight loss is hard to achieve in obese adolescents, as we showed in the TODAY study.”
The number of adverse events reported by patients was similar in the treatment and placebo groups (85% and 81%, respectively), but the overall rates of adverse events and gastrointestinal adverse events were higher with liraglutide.
“I use liraglutide just for weight reduction because I mainly see a lot of kids with obesity. Many kids are not responding because of the GI effects of this drug. I think the weight loss could have been better had the investigators moved to a dose of 1.8 mg, which we use in adults.”
A fasting plasma glucose of 6.1 mmol/L was the primary reason for participants remaining on a lower dose of liraglutide, she said. At the same time, liraglutide concentration data indicated a high rate of noncompliance, which was expected in this population. “That’s a big problem we face with children,” Dr. Caprio said. “Some of them are not constantly taking the medication. They skip doses a lot. But that happens with patients in this age group.”
“Finally, we have something else to help children and teenagers to delay the complications we are seeing,” Dr. Caprio said. “To me, I think this is a new era. I have hope. It will be interesting to see whether liraglutide and perhaps SGLT2 [sodium-glucose transporter 2] inhibitors can delay the onset of type 2 diabetes in children. In my view, we will be doing this with drugs. I don’t think the weight loss [concerns are] going to go away without medication, unfortunately.”
Dr. Caprio reported having no financial disclosures.
LOS ANGELES – Until the recent approval of liraglutide for the treatment of children and adolescents with type 2 diabetes, investigators like Sonia Caprio, MD, were at their wits’ end watching the beta-cell function of their patients decline on metformin treatment.
“The kids were not doing well. It was like they were being treated with water,” Dr. Caprio, a pediatric endocrinologist at Yale University, New Haven, Conn., said at the annual World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease.
For example, in the NIH-funded TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study that began enrollment in 2004, 699 patients aged between 10 and 17 years and with type 2 diabetes were treated with metformin (1,000 mg, twice daily) to attain a glycated hemoglobin level of less than 8% and were then randomly assigned to continued treatment with metformin alone or to metformin combined with rosiglitazone (4 mg, twice a day) or a lifestyle-intervention program that focused on weight loss through modifying eating and activity behaviors (N Engl J Med. 2012;366:2247-56).
Over the course of 11 months, the researchers found that 46% of the children were failing treatment. “The worst arm was the metformin arm,” said Dr. Caprio, who was involved with the study. “Kids were not responding to the drug at all. About 52% of children failed to do better using metformin – a classic drug that we all start kids on when we diagnose them with type 2 diabetes.”
Findings from a follow-up study, TODAY2, showed that these young patients were prone to serious diabetes-related events, such as heart attacks, chronic kidney disease, retinal disease, neuropathy, and complications in the offspring of pregnancies.
In addition, results from the RISE (Restoring Insulin Secretion) Pediatric Medication Study found that, in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes, neither 3 months of insulin glargine followed by 9 months of metformin nor 12 months of metformin alone halted the progressive deterioration of beta-cell function (Diabetes Care. 2018 Aug; 41[8]:1717-25).
“The uniqueness of RISE is that we employed very sophisticated techniques to measure insulin secretion and sensitivity while they were being treated with these usual drugs,” said Dr. Caprio, who was one of the study investigators. “The beta cell is unresponsive to metformin and other treatments. The question is, why?”
Despite these findings, 2018 consensus guidelines from the American Diabetes Association on the evaluation and management of youth-onset diabetes (Diabetes Care. 2018;41:2648-68) call for the administration of metformin twice daily in youth with new-onset diabetes who have a hemoglobin A1c (HbA1c) level of less than 8.5%. “I argue that is not the way. We need better ways to treat [these patients] because they are moving fast to having complications,” she said.
Enter the Ellipse Trial, a pivotal multicenter, randomized study that evaluated the effect of the glucagonlike peptide-1 receptor agonist liraglutide in children and adolescents with type 2 diabetes (N Engl J Med. 2019;381:637-46).
Researchers, led by William V. Tamborlane, MD, chief of Yale Medicine Pediatric Endocrinology, also in New Haven, randomized 135 patients to one of two arms: 66 to subcutaneous liraglutide (up to 1.8 mg/day) and 69 to placebo for a 26-week, double-blind period, followed by a 26-week open-label extension period. All patients received metformin during the trial. More than half of the study participants (62%) were female, the mean age was 15 years, 65% were white, the mean body mass index was 33.9 kg/m2, their mean fasting glucose was 8.4 mmol/L, and their mean HbA1c was 7.8%.
for an estimated treatment difference of −1.06 percentage points (P less than .001). By 52 weeks, the difference increased to −1.30 percentage points.
“There was also a significant drop in BMI z score in patients treated with liraglutide, which is important,” Dr. Caprio said. “This medication is having an impact on weight, which is a key driver of the onset of type 2 diabetes in youth. This is a remarkable achievement because weight loss is hard to achieve in obese adolescents, as we showed in the TODAY study.”
The number of adverse events reported by patients was similar in the treatment and placebo groups (85% and 81%, respectively), but the overall rates of adverse events and gastrointestinal adverse events were higher with liraglutide.
“I use liraglutide just for weight reduction because I mainly see a lot of kids with obesity. Many kids are not responding because of the GI effects of this drug. I think the weight loss could have been better had the investigators moved to a dose of 1.8 mg, which we use in adults.”
A fasting plasma glucose of 6.1 mmol/L was the primary reason for participants remaining on a lower dose of liraglutide, she said. At the same time, liraglutide concentration data indicated a high rate of noncompliance, which was expected in this population. “That’s a big problem we face with children,” Dr. Caprio said. “Some of them are not constantly taking the medication. They skip doses a lot. But that happens with patients in this age group.”
“Finally, we have something else to help children and teenagers to delay the complications we are seeing,” Dr. Caprio said. “To me, I think this is a new era. I have hope. It will be interesting to see whether liraglutide and perhaps SGLT2 [sodium-glucose transporter 2] inhibitors can delay the onset of type 2 diabetes in children. In my view, we will be doing this with drugs. I don’t think the weight loss [concerns are] going to go away without medication, unfortunately.”
Dr. Caprio reported having no financial disclosures.
EXPERT ANALYSIS FROM THE WCIRDC 2019
Do women with diabetes need more CVD risk reduction than men?
BUSAN, SOUTH KOREA – Whether cardiovascular disease risk reduction efforts should be more aggressive in women than men with diabetes depends on how you interpret the data.
Two experts came to different conclusions on this question during a heated, but jovial, debate last week here at the International Diabetes Federation 2019 Congress.
Endocrinologist David Simmons, MB, BChir, Western Sydney University, Campbelltown, Australia, argued that diabetes erases the well-described life expectancy advantage of 4-7 years that women experience over men in the general population.
He also highlighted the fact that the heightened risk is of particular concern in both younger women and those with prior gestational diabetes.
But Timothy Davis, BMedSc, MB, BS, DPhil, an endocrinologist and general physician at Fremantle (Australia) Hospital, countered that the data only show the diabetes-attributable excess cardiovascular risk is higher in women than men, but that the absolute risk is actually greater in men.
Moreover, he argued, at least in type 1 diabetes, there is no evidence that more aggressive cardiovascular risk factor management improves outcomes.
Yes: Diabetes eliminates female CVD protection
Dr. Simmons began by pointing out that, although on average women die at an older age than men, it has been known for over 40 years that this “female protection” is lost in insulin-treated women, particularly as a result of their increased risk for cardiovascular disease.
In a 2015 meta-analysis of 26 studies, women with type 1 diabetes were found to have about a 37% greater risk of all-cause mortality, compared with men with the condition when mortality is contrasted with that of the general population, and twice the risk of both fatal and nonfatal vascular events.
The risk appeared to be greater in women who were younger at the time of diabetes diagnosis. “This is a really important point – the time we would want to intervene,” Dr. Simmons said.
In another meta-analysis of 30 studies including 2,307,694 individuals with type 2 diabetes and 252,491 deaths, the pooled women-to-men ratio of the standardized mortality ratio for all-cause mortality was 1.14.
In those with versus without type 2 diabetes, the pooled standardized mortality ratio in women was 2.30 and in men was 1.94, both significant, compared with those without diabetes.
And in a 2006 meta-analysis of 22 studies involving individuals with type 2 diabetes, the pooled data showed a 46% excess relative risk using standardized mortality ratios in women versus men for fatal coronary artery disease.
Meanwhile, in a 2018 meta-analysis of 68 studies involving nearly 1 million adults examining differences in occlusive vascular disease, after controlling for major vascular risk factors, diabetes roughly doubled the risk for occlusive vascular mortality in men (relative risk, 2.10), but tripled it in women (3.00).
Women with diabetes aged 35-59 years had the highest relative risk for death over follow-up across all age and sex groups: They had 5.5 times the excess risk, compared with those without diabetes, while the excess risk for men of that age was 2.3-fold.
“So very clearly, it’s these young women who are most at risk, “emphasized Dr. Simmons, who is an investigator for Novo Nordisk and a speaker for Medtronic, Novo Nordisk, and Sanofi.
Are disparities because of differences in cvd risk factor management?
The question has arisen whether the female/male differences might be because of differences in cardiovascular risk factor management, Simmons noted.
A 2015 American Heart Association statement laid out the evidence for lower prescribing of statins, aspirin, beta-blockers, and ACE inhibitors in women, compared with men, Dr. Simmons said.
And some studies suggest medication adherence is lower in women than men.
In terms of medications, fenofibrate appears to produce better outcomes in women than men, but there is no evidence of gender differences in the effects of statins, ACE inhibitors, or aspirin, Simmons said.
He also outlined the results of a 2008 study of 78,254 patients with acute myocardial infarction from 420 U.S. hospitals in 2001-2006.
Women were older, had more comorbidities, less often presented with ST-elevation myocardial infarction (STEMI), and had a higher rate of unadjusted in-hospital death (8.2% vs. 5.7%; P less than .0001) than men. Of the participants, 33% of women had diabetes, compared with 28% of men.
The in-hospital mortality difference disappeared after multivariable adjustment, but women with STEMI still had higher adjusted mortality rates than men.
“The underuse of evidence-based treatments and delayed reperfusion in women represent potential opportunities for reducing sex disparities in care and outcome after acute myocardial infarction,” the authors concluded.
“It’s very clear amongst our cardiology colleagues that something needs to be done and that we need more aggressive cardiological risk reduction in women,” Dr. Simmons said.
“The AHA has already decided this. It’s already a policy. So why are we having this debate?” he wondered.
He also pointed out that women with prior gestational diabetes are an exceptionally high–risk group, with a twofold excess risk for cardiovascular disease within the first 10 years post partum.
“We need to do something about this particularly high-risk group, independent of debates about gender,” Dr. Simmons emphasized. “Clearly, women with diabetes warrant more aggressive cardiovascular risk reduction than men with diabetes, especially at those younger ages,” he concluded.
No: Confusion about relative risk within each sex and absolute risk
Dr. Davis began his counterargument by stating that estimation of absolute vascular risk is an established part of strategies to prevent cardiovascular disease, including in diabetes.
And that risk, he stressed, is actually higher in men.
“Male sex is a consistent adverse risk factor in cardiovascular disease event prediction equations in type 2 diabetes. Identifying absolute risk is important,” he said, noting risk calculators include male sex, such as the risk engine derived from the United Kingdom Prospective Diabetes Trial.
And in the Australian population-based Fremantle study, of which Dr. Davis is an author, the absolute 5-year incidence rates for all outcomes – including myocardial infarction, stroke, heart failure, lower extremity amputation, cardiovascular mortality, and all-cause mortality – were consistently higher in men versus women in the first phase, which began in the 1990s and included 1,426 individuals with diabetes (91% had type 2 diabetes).
In the ongoing second phase, which began in 2008 with 1,732 participants, overall rates of those outcomes are lower and the discrepancy between men and women has narrowed, Dr. Davis noted.
Overall, the Fremantle study data “suggest that women with type 2 diabetes do not need more aggressive cardiovascular reduction than men with type 2 diabetes because they are not at increased absolute vascular risk,” he stressed.
And in a “sensitivity analysis” of two areas in Finland, the authors concluded that the stronger effect of type 2 diabetes on the risk of congenital heart disease (CHD) in women, compared with men was in part explained by a heavier risk factor burden and a greater effect of blood pressure and atherogenic dyslipidemia in women with diabetes, he explained.
The Finnish authors wrote, “In terms of absolute risk of CHD death or a major CHD event, diabetes almost completely abolished the female protection from CHD.”
But, Dr. Davis emphasized, rates were not higher in females.
So then, “why is there the view that women with type 2 diabetes need more aggressive cardiovascular risk reduction than men with diabetes?
“It probably comes back to confusion based on absolute risk versus a comparison of relative risk within each sex,” he asserted.
ADA Standards of Medical Care 2019 don’t mention gender
Lastly, in a meta-analysis published just in July this year involving more than 5 million participants, compared with men with diabetes, women with diabetes had a 58% and 13% greater risk of CHD and all-cause mortality, respectively.
“This points to an urgent need to develop sex- and gender-specific risk assessment strategies and therapeutic interventions that target diabetes management in the context of CHD prevention,” the authors concluded.
But, Dr. Davis noted, “It is not absolute vascular risk. It’s a relative risk compared across the two genders. In the paper, there is no mention of absolute vascular risk.
“Greater CVD mortality in women with and without diabetes, versus men, doesn’t mean there’s also an absolute vascular increase in women versus men with diabetes,” he said.
Moreover, Dr. Davis pointed out that in an editorial accompanying the 2015 meta-analysis in type 1 diabetes, Simmons had actually stated that absolute mortality rates are highest in men.
“I don’t know what happened to his epidemiology knowledge in the last 4 years but it seems to have gone backwards,” he joked to his debate opponent.
And, Dr. Davis asserted, even if there were a higher risk in women with type 1 diabetes, there is no evidence that cardiovascular risk reduction measures affect endpoints in that patient population. Only about 8% of people with diabetes in statin trials had type 1 diabetes.
Indeed, he noted, in the American Diabetes Association Standards of Medical Care in Diabetes – 2019, the treatment goals for individual cardiovascular risk factors do not mention gender.
What’s more, Dr. David said, there is evidence that women are significantly less likely than men to take prescribed statins and are more likely to have an eating disorder and underdose insulin, “suggesting significant issues with compliance. ... So, trying to get more intensive risk reduction in women may be a challenge.”
“Women with diabetes do not need more aggressive cardiovascular risk reduction than men with diabetes, irrespective of type,” he concluded.
A version of this story originally appeared on medscape.com.
BUSAN, SOUTH KOREA – Whether cardiovascular disease risk reduction efforts should be more aggressive in women than men with diabetes depends on how you interpret the data.
Two experts came to different conclusions on this question during a heated, but jovial, debate last week here at the International Diabetes Federation 2019 Congress.
Endocrinologist David Simmons, MB, BChir, Western Sydney University, Campbelltown, Australia, argued that diabetes erases the well-described life expectancy advantage of 4-7 years that women experience over men in the general population.
He also highlighted the fact that the heightened risk is of particular concern in both younger women and those with prior gestational diabetes.
But Timothy Davis, BMedSc, MB, BS, DPhil, an endocrinologist and general physician at Fremantle (Australia) Hospital, countered that the data only show the diabetes-attributable excess cardiovascular risk is higher in women than men, but that the absolute risk is actually greater in men.
Moreover, he argued, at least in type 1 diabetes, there is no evidence that more aggressive cardiovascular risk factor management improves outcomes.
Yes: Diabetes eliminates female CVD protection
Dr. Simmons began by pointing out that, although on average women die at an older age than men, it has been known for over 40 years that this “female protection” is lost in insulin-treated women, particularly as a result of their increased risk for cardiovascular disease.
In a 2015 meta-analysis of 26 studies, women with type 1 diabetes were found to have about a 37% greater risk of all-cause mortality, compared with men with the condition when mortality is contrasted with that of the general population, and twice the risk of both fatal and nonfatal vascular events.
The risk appeared to be greater in women who were younger at the time of diabetes diagnosis. “This is a really important point – the time we would want to intervene,” Dr. Simmons said.
In another meta-analysis of 30 studies including 2,307,694 individuals with type 2 diabetes and 252,491 deaths, the pooled women-to-men ratio of the standardized mortality ratio for all-cause mortality was 1.14.
In those with versus without type 2 diabetes, the pooled standardized mortality ratio in women was 2.30 and in men was 1.94, both significant, compared with those without diabetes.
And in a 2006 meta-analysis of 22 studies involving individuals with type 2 diabetes, the pooled data showed a 46% excess relative risk using standardized mortality ratios in women versus men for fatal coronary artery disease.
Meanwhile, in a 2018 meta-analysis of 68 studies involving nearly 1 million adults examining differences in occlusive vascular disease, after controlling for major vascular risk factors, diabetes roughly doubled the risk for occlusive vascular mortality in men (relative risk, 2.10), but tripled it in women (3.00).
Women with diabetes aged 35-59 years had the highest relative risk for death over follow-up across all age and sex groups: They had 5.5 times the excess risk, compared with those without diabetes, while the excess risk for men of that age was 2.3-fold.
“So very clearly, it’s these young women who are most at risk, “emphasized Dr. Simmons, who is an investigator for Novo Nordisk and a speaker for Medtronic, Novo Nordisk, and Sanofi.
Are disparities because of differences in cvd risk factor management?
The question has arisen whether the female/male differences might be because of differences in cardiovascular risk factor management, Simmons noted.
A 2015 American Heart Association statement laid out the evidence for lower prescribing of statins, aspirin, beta-blockers, and ACE inhibitors in women, compared with men, Dr. Simmons said.
And some studies suggest medication adherence is lower in women than men.
In terms of medications, fenofibrate appears to produce better outcomes in women than men, but there is no evidence of gender differences in the effects of statins, ACE inhibitors, or aspirin, Simmons said.
He also outlined the results of a 2008 study of 78,254 patients with acute myocardial infarction from 420 U.S. hospitals in 2001-2006.
Women were older, had more comorbidities, less often presented with ST-elevation myocardial infarction (STEMI), and had a higher rate of unadjusted in-hospital death (8.2% vs. 5.7%; P less than .0001) than men. Of the participants, 33% of women had diabetes, compared with 28% of men.
The in-hospital mortality difference disappeared after multivariable adjustment, but women with STEMI still had higher adjusted mortality rates than men.
“The underuse of evidence-based treatments and delayed reperfusion in women represent potential opportunities for reducing sex disparities in care and outcome after acute myocardial infarction,” the authors concluded.
“It’s very clear amongst our cardiology colleagues that something needs to be done and that we need more aggressive cardiological risk reduction in women,” Dr. Simmons said.
“The AHA has already decided this. It’s already a policy. So why are we having this debate?” he wondered.
He also pointed out that women with prior gestational diabetes are an exceptionally high–risk group, with a twofold excess risk for cardiovascular disease within the first 10 years post partum.
“We need to do something about this particularly high-risk group, independent of debates about gender,” Dr. Simmons emphasized. “Clearly, women with diabetes warrant more aggressive cardiovascular risk reduction than men with diabetes, especially at those younger ages,” he concluded.
No: Confusion about relative risk within each sex and absolute risk
Dr. Davis began his counterargument by stating that estimation of absolute vascular risk is an established part of strategies to prevent cardiovascular disease, including in diabetes.
And that risk, he stressed, is actually higher in men.
“Male sex is a consistent adverse risk factor in cardiovascular disease event prediction equations in type 2 diabetes. Identifying absolute risk is important,” he said, noting risk calculators include male sex, such as the risk engine derived from the United Kingdom Prospective Diabetes Trial.
And in the Australian population-based Fremantle study, of which Dr. Davis is an author, the absolute 5-year incidence rates for all outcomes – including myocardial infarction, stroke, heart failure, lower extremity amputation, cardiovascular mortality, and all-cause mortality – were consistently higher in men versus women in the first phase, which began in the 1990s and included 1,426 individuals with diabetes (91% had type 2 diabetes).
In the ongoing second phase, which began in 2008 with 1,732 participants, overall rates of those outcomes are lower and the discrepancy between men and women has narrowed, Dr. Davis noted.
Overall, the Fremantle study data “suggest that women with type 2 diabetes do not need more aggressive cardiovascular reduction than men with type 2 diabetes because they are not at increased absolute vascular risk,” he stressed.
And in a “sensitivity analysis” of two areas in Finland, the authors concluded that the stronger effect of type 2 diabetes on the risk of congenital heart disease (CHD) in women, compared with men was in part explained by a heavier risk factor burden and a greater effect of blood pressure and atherogenic dyslipidemia in women with diabetes, he explained.
The Finnish authors wrote, “In terms of absolute risk of CHD death or a major CHD event, diabetes almost completely abolished the female protection from CHD.”
But, Dr. Davis emphasized, rates were not higher in females.
So then, “why is there the view that women with type 2 diabetes need more aggressive cardiovascular risk reduction than men with diabetes?
“It probably comes back to confusion based on absolute risk versus a comparison of relative risk within each sex,” he asserted.
ADA Standards of Medical Care 2019 don’t mention gender
Lastly, in a meta-analysis published just in July this year involving more than 5 million participants, compared with men with diabetes, women with diabetes had a 58% and 13% greater risk of CHD and all-cause mortality, respectively.
“This points to an urgent need to develop sex- and gender-specific risk assessment strategies and therapeutic interventions that target diabetes management in the context of CHD prevention,” the authors concluded.
But, Dr. Davis noted, “It is not absolute vascular risk. It’s a relative risk compared across the two genders. In the paper, there is no mention of absolute vascular risk.
“Greater CVD mortality in women with and without diabetes, versus men, doesn’t mean there’s also an absolute vascular increase in women versus men with diabetes,” he said.
Moreover, Dr. Davis pointed out that in an editorial accompanying the 2015 meta-analysis in type 1 diabetes, Simmons had actually stated that absolute mortality rates are highest in men.
“I don’t know what happened to his epidemiology knowledge in the last 4 years but it seems to have gone backwards,” he joked to his debate opponent.
And, Dr. Davis asserted, even if there were a higher risk in women with type 1 diabetes, there is no evidence that cardiovascular risk reduction measures affect endpoints in that patient population. Only about 8% of people with diabetes in statin trials had type 1 diabetes.
Indeed, he noted, in the American Diabetes Association Standards of Medical Care in Diabetes – 2019, the treatment goals for individual cardiovascular risk factors do not mention gender.
What’s more, Dr. David said, there is evidence that women are significantly less likely than men to take prescribed statins and are more likely to have an eating disorder and underdose insulin, “suggesting significant issues with compliance. ... So, trying to get more intensive risk reduction in women may be a challenge.”
“Women with diabetes do not need more aggressive cardiovascular risk reduction than men with diabetes, irrespective of type,” he concluded.
A version of this story originally appeared on medscape.com.
BUSAN, SOUTH KOREA – Whether cardiovascular disease risk reduction efforts should be more aggressive in women than men with diabetes depends on how you interpret the data.
Two experts came to different conclusions on this question during a heated, but jovial, debate last week here at the International Diabetes Federation 2019 Congress.
Endocrinologist David Simmons, MB, BChir, Western Sydney University, Campbelltown, Australia, argued that diabetes erases the well-described life expectancy advantage of 4-7 years that women experience over men in the general population.
He also highlighted the fact that the heightened risk is of particular concern in both younger women and those with prior gestational diabetes.
But Timothy Davis, BMedSc, MB, BS, DPhil, an endocrinologist and general physician at Fremantle (Australia) Hospital, countered that the data only show the diabetes-attributable excess cardiovascular risk is higher in women than men, but that the absolute risk is actually greater in men.
Moreover, he argued, at least in type 1 diabetes, there is no evidence that more aggressive cardiovascular risk factor management improves outcomes.
Yes: Diabetes eliminates female CVD protection
Dr. Simmons began by pointing out that, although on average women die at an older age than men, it has been known for over 40 years that this “female protection” is lost in insulin-treated women, particularly as a result of their increased risk for cardiovascular disease.
In a 2015 meta-analysis of 26 studies, women with type 1 diabetes were found to have about a 37% greater risk of all-cause mortality, compared with men with the condition when mortality is contrasted with that of the general population, and twice the risk of both fatal and nonfatal vascular events.
The risk appeared to be greater in women who were younger at the time of diabetes diagnosis. “This is a really important point – the time we would want to intervene,” Dr. Simmons said.
In another meta-analysis of 30 studies including 2,307,694 individuals with type 2 diabetes and 252,491 deaths, the pooled women-to-men ratio of the standardized mortality ratio for all-cause mortality was 1.14.
In those with versus without type 2 diabetes, the pooled standardized mortality ratio in women was 2.30 and in men was 1.94, both significant, compared with those without diabetes.
And in a 2006 meta-analysis of 22 studies involving individuals with type 2 diabetes, the pooled data showed a 46% excess relative risk using standardized mortality ratios in women versus men for fatal coronary artery disease.
Meanwhile, in a 2018 meta-analysis of 68 studies involving nearly 1 million adults examining differences in occlusive vascular disease, after controlling for major vascular risk factors, diabetes roughly doubled the risk for occlusive vascular mortality in men (relative risk, 2.10), but tripled it in women (3.00).
Women with diabetes aged 35-59 years had the highest relative risk for death over follow-up across all age and sex groups: They had 5.5 times the excess risk, compared with those without diabetes, while the excess risk for men of that age was 2.3-fold.
“So very clearly, it’s these young women who are most at risk, “emphasized Dr. Simmons, who is an investigator for Novo Nordisk and a speaker for Medtronic, Novo Nordisk, and Sanofi.
Are disparities because of differences in cvd risk factor management?
The question has arisen whether the female/male differences might be because of differences in cardiovascular risk factor management, Simmons noted.
A 2015 American Heart Association statement laid out the evidence for lower prescribing of statins, aspirin, beta-blockers, and ACE inhibitors in women, compared with men, Dr. Simmons said.
And some studies suggest medication adherence is lower in women than men.
In terms of medications, fenofibrate appears to produce better outcomes in women than men, but there is no evidence of gender differences in the effects of statins, ACE inhibitors, or aspirin, Simmons said.
He also outlined the results of a 2008 study of 78,254 patients with acute myocardial infarction from 420 U.S. hospitals in 2001-2006.
Women were older, had more comorbidities, less often presented with ST-elevation myocardial infarction (STEMI), and had a higher rate of unadjusted in-hospital death (8.2% vs. 5.7%; P less than .0001) than men. Of the participants, 33% of women had diabetes, compared with 28% of men.
The in-hospital mortality difference disappeared after multivariable adjustment, but women with STEMI still had higher adjusted mortality rates than men.
“The underuse of evidence-based treatments and delayed reperfusion in women represent potential opportunities for reducing sex disparities in care and outcome after acute myocardial infarction,” the authors concluded.
“It’s very clear amongst our cardiology colleagues that something needs to be done and that we need more aggressive cardiological risk reduction in women,” Dr. Simmons said.
“The AHA has already decided this. It’s already a policy. So why are we having this debate?” he wondered.
He also pointed out that women with prior gestational diabetes are an exceptionally high–risk group, with a twofold excess risk for cardiovascular disease within the first 10 years post partum.
“We need to do something about this particularly high-risk group, independent of debates about gender,” Dr. Simmons emphasized. “Clearly, women with diabetes warrant more aggressive cardiovascular risk reduction than men with diabetes, especially at those younger ages,” he concluded.
No: Confusion about relative risk within each sex and absolute risk
Dr. Davis began his counterargument by stating that estimation of absolute vascular risk is an established part of strategies to prevent cardiovascular disease, including in diabetes.
And that risk, he stressed, is actually higher in men.
“Male sex is a consistent adverse risk factor in cardiovascular disease event prediction equations in type 2 diabetes. Identifying absolute risk is important,” he said, noting risk calculators include male sex, such as the risk engine derived from the United Kingdom Prospective Diabetes Trial.
And in the Australian population-based Fremantle study, of which Dr. Davis is an author, the absolute 5-year incidence rates for all outcomes – including myocardial infarction, stroke, heart failure, lower extremity amputation, cardiovascular mortality, and all-cause mortality – were consistently higher in men versus women in the first phase, which began in the 1990s and included 1,426 individuals with diabetes (91% had type 2 diabetes).
In the ongoing second phase, which began in 2008 with 1,732 participants, overall rates of those outcomes are lower and the discrepancy between men and women has narrowed, Dr. Davis noted.
Overall, the Fremantle study data “suggest that women with type 2 diabetes do not need more aggressive cardiovascular reduction than men with type 2 diabetes because they are not at increased absolute vascular risk,” he stressed.
And in a “sensitivity analysis” of two areas in Finland, the authors concluded that the stronger effect of type 2 diabetes on the risk of congenital heart disease (CHD) in women, compared with men was in part explained by a heavier risk factor burden and a greater effect of blood pressure and atherogenic dyslipidemia in women with diabetes, he explained.
The Finnish authors wrote, “In terms of absolute risk of CHD death or a major CHD event, diabetes almost completely abolished the female protection from CHD.”
But, Dr. Davis emphasized, rates were not higher in females.
So then, “why is there the view that women with type 2 diabetes need more aggressive cardiovascular risk reduction than men with diabetes?
“It probably comes back to confusion based on absolute risk versus a comparison of relative risk within each sex,” he asserted.
ADA Standards of Medical Care 2019 don’t mention gender
Lastly, in a meta-analysis published just in July this year involving more than 5 million participants, compared with men with diabetes, women with diabetes had a 58% and 13% greater risk of CHD and all-cause mortality, respectively.
“This points to an urgent need to develop sex- and gender-specific risk assessment strategies and therapeutic interventions that target diabetes management in the context of CHD prevention,” the authors concluded.
But, Dr. Davis noted, “It is not absolute vascular risk. It’s a relative risk compared across the two genders. In the paper, there is no mention of absolute vascular risk.
“Greater CVD mortality in women with and without diabetes, versus men, doesn’t mean there’s also an absolute vascular increase in women versus men with diabetes,” he said.
Moreover, Dr. Davis pointed out that in an editorial accompanying the 2015 meta-analysis in type 1 diabetes, Simmons had actually stated that absolute mortality rates are highest in men.
“I don’t know what happened to his epidemiology knowledge in the last 4 years but it seems to have gone backwards,” he joked to his debate opponent.
And, Dr. Davis asserted, even if there were a higher risk in women with type 1 diabetes, there is no evidence that cardiovascular risk reduction measures affect endpoints in that patient population. Only about 8% of people with diabetes in statin trials had type 1 diabetes.
Indeed, he noted, in the American Diabetes Association Standards of Medical Care in Diabetes – 2019, the treatment goals for individual cardiovascular risk factors do not mention gender.
What’s more, Dr. David said, there is evidence that women are significantly less likely than men to take prescribed statins and are more likely to have an eating disorder and underdose insulin, “suggesting significant issues with compliance. ... So, trying to get more intensive risk reduction in women may be a challenge.”
“Women with diabetes do not need more aggressive cardiovascular risk reduction than men with diabetes, irrespective of type,” he concluded.
A version of this story originally appeared on medscape.com.