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Skin reactions common at insulin pump infusion sites
new research suggests.
Insulin pump use is increasingly common, but many patients experience infusion-site failure that in some cases leads to discontinuation. In a novel investigation, researchers at the University of Washington, Seattle, used biopsies and noninvasive imaging to compare insulin pump sites with control sites in 30 patients. Several differences were found at pump sites in comparison with control sites, including fibrosis, inflammation, eosinophils, and increased vessel density.
“These findings support allergic sensitization as a potentially common reaction at [insulin pump] sites. The leading candidates causing this include insulin preservatives, plastic materials, and adhesive glue used in device manufacturing,” wrote Andrea Kalus, MD, of the university’s dermatology division, and colleagues. The findings were published recently in Diabetes Care.
The inflammatory response, they wrote, “may result in tissue changes responsible for the infusion-site failures seen frequently in clinical practice.”
Such infusion site problems represent an “Achilles heel” of these otherwise highly beneficial devices, lead author Irl Hirsch, MD, professor of medicine in the division of metabolism, endocrinology, and nutrition, said in a statement. “It doesn’t really matter how good the technology is. We still don’t understand what is happening with the infusion sites, much less to [be able to] fix it.”
Significant differences between pump and nonpump sites
In the cross-sectional study, Dr. Kalus and colleagues used noninvasive optical coherence tomography (OCT) immediately prior to performing punch biopsies at three sites: the site currently in active use, the “recovery site” used 3-5 days prior to the procedures, and control sites never used for pump infusion. Punch biopsies were also performed at those sites.
The mean age of the patients was 48.3 years, the mean diabetes duration was 30.4 years, and the mean duration of pump use was 15.8 years. Nearly all patients (93.3%) reported itchiness at the site, and 76.7% reported skin redness.
Of the 25 patients for whom OCT imaging was successful, statistical analysis showed significant differences in vascular area density and the optical attenuation coefficient, a surrogate for skin inflammation, between the pump and control sites and between recovery sites and current pump sites. The greater vessel density is likely a result of injury and repair related to catheter insertion, the authors said.
In the biopsy samples, both current and recovery sites showed increased fibrosis, fibrin, inflammation, fat necrosis, vascularity, and eosinophils, compared with the control sites, but no significant differences were found between current and recovery sites.
Eosinophils: ‘The most surprising histologic finding’
Eosinophils were found in 73% of skin biopsy specimens from current sites and in 75% of specimens from recovery sites, compared with none from the control sites (for both, P < .01). In all study participants, eosinophils were found in at least one current and/or recovery infusion site deep in the dermis near the interface with fat. The number of eosinophils ranged from 0 to 31 per high-power field, with a median of 4.
The number of eosinophils didn’t vary by type of insulin or brand of pump, but higher counts were seen in those who had used pumps for less than 10 years, compared with more than 20 years (P = .02).
The prevalence and degree of eosinophils were “the most surprising histologic finding,” the authors wrote, adding that “eosinophils are not typically present as a component of resident inflammatory cells in the skin.”
While eosinophils may be present in normal wound healing, “the absolute number and density of eosinophil in these samples support a delayed-type hypersensitivity response, which is typically observed between 2 and 7 days after exposure to an allergen. ... Eosinophils are often correlated with symptoms of itchiness and likely explain the high percentage of participants who reported itchiness in this study,” Dr. Kalus and colleagues wrote.
Correlation found between inflammation and glycemic control
All participants used the Dexcom G6 continuous glucose monitor as part of their usual care. Inflammation scores were positively correlated with insulin dose (P = .009) and were negatively correlated with time in range (P = .01).
No other OCT or biopsy findings differed by duration of pump use, previous use of animal insulin, or type of insulin.
The reason for these findings is unclear, Dr. Hirsch said. “How much was the catheter or the insulin causing the irritation around the sites? How much was it from the preservatives, or is this because of the insulin pump itself? All these questions need to be answered in future studies. ... The real goal of all of this is to minimize skin damage and improve the experience for our patients.”
The study was funded by the Leona M. and Harry B. Helmsley Charitable Trust. Dr. Hirsch reported grants and contracts from Insulet, Medtronic, and Dexcom outside the submitted work; consulting fees from Abbott Diabetes Care, Lifescan, and Hagar outside the submitted work; and honoraria for lectures, presentations, participation on speaker’s bureaus, manuscript writing, or educational events as section editor for UpToDate outside the submitted work. Dr. Kalus has no disclosures.
A version of this article first appeared on Medscape.com.
new research suggests.
Insulin pump use is increasingly common, but many patients experience infusion-site failure that in some cases leads to discontinuation. In a novel investigation, researchers at the University of Washington, Seattle, used biopsies and noninvasive imaging to compare insulin pump sites with control sites in 30 patients. Several differences were found at pump sites in comparison with control sites, including fibrosis, inflammation, eosinophils, and increased vessel density.
“These findings support allergic sensitization as a potentially common reaction at [insulin pump] sites. The leading candidates causing this include insulin preservatives, plastic materials, and adhesive glue used in device manufacturing,” wrote Andrea Kalus, MD, of the university’s dermatology division, and colleagues. The findings were published recently in Diabetes Care.
The inflammatory response, they wrote, “may result in tissue changes responsible for the infusion-site failures seen frequently in clinical practice.”
Such infusion site problems represent an “Achilles heel” of these otherwise highly beneficial devices, lead author Irl Hirsch, MD, professor of medicine in the division of metabolism, endocrinology, and nutrition, said in a statement. “It doesn’t really matter how good the technology is. We still don’t understand what is happening with the infusion sites, much less to [be able to] fix it.”
Significant differences between pump and nonpump sites
In the cross-sectional study, Dr. Kalus and colleagues used noninvasive optical coherence tomography (OCT) immediately prior to performing punch biopsies at three sites: the site currently in active use, the “recovery site” used 3-5 days prior to the procedures, and control sites never used for pump infusion. Punch biopsies were also performed at those sites.
The mean age of the patients was 48.3 years, the mean diabetes duration was 30.4 years, and the mean duration of pump use was 15.8 years. Nearly all patients (93.3%) reported itchiness at the site, and 76.7% reported skin redness.
Of the 25 patients for whom OCT imaging was successful, statistical analysis showed significant differences in vascular area density and the optical attenuation coefficient, a surrogate for skin inflammation, between the pump and control sites and between recovery sites and current pump sites. The greater vessel density is likely a result of injury and repair related to catheter insertion, the authors said.
In the biopsy samples, both current and recovery sites showed increased fibrosis, fibrin, inflammation, fat necrosis, vascularity, and eosinophils, compared with the control sites, but no significant differences were found between current and recovery sites.
Eosinophils: ‘The most surprising histologic finding’
Eosinophils were found in 73% of skin biopsy specimens from current sites and in 75% of specimens from recovery sites, compared with none from the control sites (for both, P < .01). In all study participants, eosinophils were found in at least one current and/or recovery infusion site deep in the dermis near the interface with fat. The number of eosinophils ranged from 0 to 31 per high-power field, with a median of 4.
The number of eosinophils didn’t vary by type of insulin or brand of pump, but higher counts were seen in those who had used pumps for less than 10 years, compared with more than 20 years (P = .02).
The prevalence and degree of eosinophils were “the most surprising histologic finding,” the authors wrote, adding that “eosinophils are not typically present as a component of resident inflammatory cells in the skin.”
While eosinophils may be present in normal wound healing, “the absolute number and density of eosinophil in these samples support a delayed-type hypersensitivity response, which is typically observed between 2 and 7 days after exposure to an allergen. ... Eosinophils are often correlated with symptoms of itchiness and likely explain the high percentage of participants who reported itchiness in this study,” Dr. Kalus and colleagues wrote.
Correlation found between inflammation and glycemic control
All participants used the Dexcom G6 continuous glucose monitor as part of their usual care. Inflammation scores were positively correlated with insulin dose (P = .009) and were negatively correlated with time in range (P = .01).
No other OCT or biopsy findings differed by duration of pump use, previous use of animal insulin, or type of insulin.
The reason for these findings is unclear, Dr. Hirsch said. “How much was the catheter or the insulin causing the irritation around the sites? How much was it from the preservatives, or is this because of the insulin pump itself? All these questions need to be answered in future studies. ... The real goal of all of this is to minimize skin damage and improve the experience for our patients.”
The study was funded by the Leona M. and Harry B. Helmsley Charitable Trust. Dr. Hirsch reported grants and contracts from Insulet, Medtronic, and Dexcom outside the submitted work; consulting fees from Abbott Diabetes Care, Lifescan, and Hagar outside the submitted work; and honoraria for lectures, presentations, participation on speaker’s bureaus, manuscript writing, or educational events as section editor for UpToDate outside the submitted work. Dr. Kalus has no disclosures.
A version of this article first appeared on Medscape.com.
new research suggests.
Insulin pump use is increasingly common, but many patients experience infusion-site failure that in some cases leads to discontinuation. In a novel investigation, researchers at the University of Washington, Seattle, used biopsies and noninvasive imaging to compare insulin pump sites with control sites in 30 patients. Several differences were found at pump sites in comparison with control sites, including fibrosis, inflammation, eosinophils, and increased vessel density.
“These findings support allergic sensitization as a potentially common reaction at [insulin pump] sites. The leading candidates causing this include insulin preservatives, plastic materials, and adhesive glue used in device manufacturing,” wrote Andrea Kalus, MD, of the university’s dermatology division, and colleagues. The findings were published recently in Diabetes Care.
The inflammatory response, they wrote, “may result in tissue changes responsible for the infusion-site failures seen frequently in clinical practice.”
Such infusion site problems represent an “Achilles heel” of these otherwise highly beneficial devices, lead author Irl Hirsch, MD, professor of medicine in the division of metabolism, endocrinology, and nutrition, said in a statement. “It doesn’t really matter how good the technology is. We still don’t understand what is happening with the infusion sites, much less to [be able to] fix it.”
Significant differences between pump and nonpump sites
In the cross-sectional study, Dr. Kalus and colleagues used noninvasive optical coherence tomography (OCT) immediately prior to performing punch biopsies at three sites: the site currently in active use, the “recovery site” used 3-5 days prior to the procedures, and control sites never used for pump infusion. Punch biopsies were also performed at those sites.
The mean age of the patients was 48.3 years, the mean diabetes duration was 30.4 years, and the mean duration of pump use was 15.8 years. Nearly all patients (93.3%) reported itchiness at the site, and 76.7% reported skin redness.
Of the 25 patients for whom OCT imaging was successful, statistical analysis showed significant differences in vascular area density and the optical attenuation coefficient, a surrogate for skin inflammation, between the pump and control sites and between recovery sites and current pump sites. The greater vessel density is likely a result of injury and repair related to catheter insertion, the authors said.
In the biopsy samples, both current and recovery sites showed increased fibrosis, fibrin, inflammation, fat necrosis, vascularity, and eosinophils, compared with the control sites, but no significant differences were found between current and recovery sites.
Eosinophils: ‘The most surprising histologic finding’
Eosinophils were found in 73% of skin biopsy specimens from current sites and in 75% of specimens from recovery sites, compared with none from the control sites (for both, P < .01). In all study participants, eosinophils were found in at least one current and/or recovery infusion site deep in the dermis near the interface with fat. The number of eosinophils ranged from 0 to 31 per high-power field, with a median of 4.
The number of eosinophils didn’t vary by type of insulin or brand of pump, but higher counts were seen in those who had used pumps for less than 10 years, compared with more than 20 years (P = .02).
The prevalence and degree of eosinophils were “the most surprising histologic finding,” the authors wrote, adding that “eosinophils are not typically present as a component of resident inflammatory cells in the skin.”
While eosinophils may be present in normal wound healing, “the absolute number and density of eosinophil in these samples support a delayed-type hypersensitivity response, which is typically observed between 2 and 7 days after exposure to an allergen. ... Eosinophils are often correlated with symptoms of itchiness and likely explain the high percentage of participants who reported itchiness in this study,” Dr. Kalus and colleagues wrote.
Correlation found between inflammation and glycemic control
All participants used the Dexcom G6 continuous glucose monitor as part of their usual care. Inflammation scores were positively correlated with insulin dose (P = .009) and were negatively correlated with time in range (P = .01).
No other OCT or biopsy findings differed by duration of pump use, previous use of animal insulin, or type of insulin.
The reason for these findings is unclear, Dr. Hirsch said. “How much was the catheter or the insulin causing the irritation around the sites? How much was it from the preservatives, or is this because of the insulin pump itself? All these questions need to be answered in future studies. ... The real goal of all of this is to minimize skin damage and improve the experience for our patients.”
The study was funded by the Leona M. and Harry B. Helmsley Charitable Trust. Dr. Hirsch reported grants and contracts from Insulet, Medtronic, and Dexcom outside the submitted work; consulting fees from Abbott Diabetes Care, Lifescan, and Hagar outside the submitted work; and honoraria for lectures, presentations, participation on speaker’s bureaus, manuscript writing, or educational events as section editor for UpToDate outside the submitted work. Dr. Kalus has no disclosures.
A version of this article first appeared on Medscape.com.
FROM DIABETES CARE
Kombucha benefits type 2 diabetes, study suggests
TOPLINE:
The sample size was too small for statistical significance.
METHODOLOGY:
- Prospective, randomized, double-blinded, crossover study at a single-center urban hospital system.
- A total of 12 participants with type 2 diabetes were randomly assigned to consume 240 mL of either a kombucha product or placebo daily with dinner for 4 weeks.
- After an 8-week washout, they were switched to the other product for another 4 weeks.
- Fasting blood glucose levels were self-determined at baseline and at 1 and 4 weeks, and questionnaires were used to assess secondary health outcomes.
- Questionnaire data were analyzed for all 12 participants, but only 7 who completed the study were included in the analysis of fasting blood glucose.
TAKEAWAY:
- Kombucha significantly lowered average fasting blood glucose levels at week 4, compared with baseline (164 vs. 116 mg/dL; P = .035), while the placebo was not associated with statistically significant change (162 vs. 141 mg/dL; P = .078).
- Among just the five participants with baseline fasting glucose > 130 mg/dL, kombucha consumption was associated with a mean fasting blood glucose decrease of 74.3 mg/dL, significantly greater than the 15.9 mg/dL drop with placebo (P = .017).
- On cultural enumeration, the kombucha contained mostly lactic acid bacteria, acetic acid bacteria, and yeast, with molds present.
IN PRACTICE:
“Kombucha is a growing part of the beverage market in the United States and the world, driven, in part, by the wide range of suggested health benefits. However, nearly all of these benefits are based on in vitro or animal studies, and human clinical trials are needed to validate biological outcomes.”
SOURCE:
The study was conducted by Chagai Mendelson, of MedStar Georgetown University Hospital, Washington, and colleagues. It was published in Frontiers in Nutrition.
LIMITATIONS:
- The number of participants was small, and attrition was high.
- Glucose levels were self-reported.
- Only one kombucha was studied.
DISCLOSURES:
One author is a cofounder of Synbiotic Health and another has a financial interest in the company. The other authors have no disclosures. Kombucha and placebo drinks were donated by Craft Kombucha, but the company did not have access to the data, and no authors have financial ties with that company.
A version of this article first appeared on Medscape.com.
TOPLINE:
The sample size was too small for statistical significance.
METHODOLOGY:
- Prospective, randomized, double-blinded, crossover study at a single-center urban hospital system.
- A total of 12 participants with type 2 diabetes were randomly assigned to consume 240 mL of either a kombucha product or placebo daily with dinner for 4 weeks.
- After an 8-week washout, they were switched to the other product for another 4 weeks.
- Fasting blood glucose levels were self-determined at baseline and at 1 and 4 weeks, and questionnaires were used to assess secondary health outcomes.
- Questionnaire data were analyzed for all 12 participants, but only 7 who completed the study were included in the analysis of fasting blood glucose.
TAKEAWAY:
- Kombucha significantly lowered average fasting blood glucose levels at week 4, compared with baseline (164 vs. 116 mg/dL; P = .035), while the placebo was not associated with statistically significant change (162 vs. 141 mg/dL; P = .078).
- Among just the five participants with baseline fasting glucose > 130 mg/dL, kombucha consumption was associated with a mean fasting blood glucose decrease of 74.3 mg/dL, significantly greater than the 15.9 mg/dL drop with placebo (P = .017).
- On cultural enumeration, the kombucha contained mostly lactic acid bacteria, acetic acid bacteria, and yeast, with molds present.
IN PRACTICE:
“Kombucha is a growing part of the beverage market in the United States and the world, driven, in part, by the wide range of suggested health benefits. However, nearly all of these benefits are based on in vitro or animal studies, and human clinical trials are needed to validate biological outcomes.”
SOURCE:
The study was conducted by Chagai Mendelson, of MedStar Georgetown University Hospital, Washington, and colleagues. It was published in Frontiers in Nutrition.
LIMITATIONS:
- The number of participants was small, and attrition was high.
- Glucose levels were self-reported.
- Only one kombucha was studied.
DISCLOSURES:
One author is a cofounder of Synbiotic Health and another has a financial interest in the company. The other authors have no disclosures. Kombucha and placebo drinks were donated by Craft Kombucha, but the company did not have access to the data, and no authors have financial ties with that company.
A version of this article first appeared on Medscape.com.
TOPLINE:
The sample size was too small for statistical significance.
METHODOLOGY:
- Prospective, randomized, double-blinded, crossover study at a single-center urban hospital system.
- A total of 12 participants with type 2 diabetes were randomly assigned to consume 240 mL of either a kombucha product or placebo daily with dinner for 4 weeks.
- After an 8-week washout, they were switched to the other product for another 4 weeks.
- Fasting blood glucose levels were self-determined at baseline and at 1 and 4 weeks, and questionnaires were used to assess secondary health outcomes.
- Questionnaire data were analyzed for all 12 participants, but only 7 who completed the study were included in the analysis of fasting blood glucose.
TAKEAWAY:
- Kombucha significantly lowered average fasting blood glucose levels at week 4, compared with baseline (164 vs. 116 mg/dL; P = .035), while the placebo was not associated with statistically significant change (162 vs. 141 mg/dL; P = .078).
- Among just the five participants with baseline fasting glucose > 130 mg/dL, kombucha consumption was associated with a mean fasting blood glucose decrease of 74.3 mg/dL, significantly greater than the 15.9 mg/dL drop with placebo (P = .017).
- On cultural enumeration, the kombucha contained mostly lactic acid bacteria, acetic acid bacteria, and yeast, with molds present.
IN PRACTICE:
“Kombucha is a growing part of the beverage market in the United States and the world, driven, in part, by the wide range of suggested health benefits. However, nearly all of these benefits are based on in vitro or animal studies, and human clinical trials are needed to validate biological outcomes.”
SOURCE:
The study was conducted by Chagai Mendelson, of MedStar Georgetown University Hospital, Washington, and colleagues. It was published in Frontiers in Nutrition.
LIMITATIONS:
- The number of participants was small, and attrition was high.
- Glucose levels were self-reported.
- Only one kombucha was studied.
DISCLOSURES:
One author is a cofounder of Synbiotic Health and another has a financial interest in the company. The other authors have no disclosures. Kombucha and placebo drinks were donated by Craft Kombucha, but the company did not have access to the data, and no authors have financial ties with that company.
A version of this article first appeared on Medscape.com.
FROM FRONTIERS IN NUTRITION
New approaches for diabetic keratopathy in the eye?
Vision loss caused by diabetes arises primarily from retinopathy, but up to 70% of people with diabetes also experience corneal problems, including keratopathy and neuropathy. Diabetic keratopathy involves impairments in epithelial wound healing, barrier function, and tear production, along with epithelial erosions and keratitis. As a result, the cornea may heal more slowly and less completely following an injury or procedures such as cataract surgery or laser therapy for diabetic retinopathy.
The abnormal wound healing is caused by impaired limbal epithelial stem cells, and the new research, published online in Diabetologia, involved isolation of those cells from 30 donor eyes of humans with and 23 without diabetes. Significant differences were found in DNA methylation between the cells of those two groups. Specifically, the WNT5A gene was hypermethylated at the promotor region in the diabetic cells and its protein markedly repressed.
However, treatment with various approaches, including exogenous WNT5A methylation inhibitors and a nanoconjugate that inhibits WNT5A suppression, improved corneal epithelial wound healing as well as expression of the limbic epithelial stem cells.
“Overall, [the] Wnt-5a [protein] is a new corneal epithelial wound healing stimulator that can be targeted to improve wound healing and stem cells in the diabetic cornea,” wrote Ruchi Shah, PhD, of the Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, and colleagues.
The finding represents more cellular changes than researchers had previously been aware of, study senior author Alexander Ljubimov, PhD, DSc, director of the eye program at the Institute, said in a statement.
“The discovery does not affect gene sequence but entails specific DNA modifications altering gene expression – what are known as epigenetic alterations,” he said.
In the experiments, treatment of the impaired diabetic limbal epithelial cells with the exogenous Wnt-5a accelerated wound healing by 1.4-fold (P < .05), compared with untreated cells and reduced healing time in diabetic organ-ultured corneas by 37% (P < .05).
Treatment with the DNA methylation inhibitor zebularine also increased levels of Wnt-5a in the diabetic limbic epithelial cells by 37% (P < .01), dose-dependently stimulated wound healing by 60% at 24 hours (P < .01), and improved wound healing by 30% in diabetic organ-cultured corneas.
The finding of Wnt-5a as a new diabetic corneal marker regulating wound healing and stem cell function may have implications for other diabetes complications involving impaired wound healing, including diabetic foot ulcers, as they share similar neurovascular, sensory, and immunological compromise with diabetic eye disease, Dr. Shah and colleagues wrote.
“Novel therapies to reverse both types of epigenetic silencing could benefit corneal function and may also prove to be beneficial in other wound healing–related diabetic complications,” they wrote.
The investigators are now working on combination therapies that target both mRNA and DNA methylation in hopes of obtaining even better wound healing.
“Our goal is to develop topical, sustained-release drugs for corneal wound healing,” said Dr. Ljubimov. “Drugs that are [Food and Drug Administration] approved and could be easily applied may be one of the most promising approaches for effective future therapies.”
This work was funded by the National Institutes of Health and the Cedars-Sinai Board of Governors Regenerative Medicine Institute. The authors reported no further disclosures.
A version of this article appeared on Medscape.com.
Vision loss caused by diabetes arises primarily from retinopathy, but up to 70% of people with diabetes also experience corneal problems, including keratopathy and neuropathy. Diabetic keratopathy involves impairments in epithelial wound healing, barrier function, and tear production, along with epithelial erosions and keratitis. As a result, the cornea may heal more slowly and less completely following an injury or procedures such as cataract surgery or laser therapy for diabetic retinopathy.
The abnormal wound healing is caused by impaired limbal epithelial stem cells, and the new research, published online in Diabetologia, involved isolation of those cells from 30 donor eyes of humans with and 23 without diabetes. Significant differences were found in DNA methylation between the cells of those two groups. Specifically, the WNT5A gene was hypermethylated at the promotor region in the diabetic cells and its protein markedly repressed.
However, treatment with various approaches, including exogenous WNT5A methylation inhibitors and a nanoconjugate that inhibits WNT5A suppression, improved corneal epithelial wound healing as well as expression of the limbic epithelial stem cells.
“Overall, [the] Wnt-5a [protein] is a new corneal epithelial wound healing stimulator that can be targeted to improve wound healing and stem cells in the diabetic cornea,” wrote Ruchi Shah, PhD, of the Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, and colleagues.
The finding represents more cellular changes than researchers had previously been aware of, study senior author Alexander Ljubimov, PhD, DSc, director of the eye program at the Institute, said in a statement.
“The discovery does not affect gene sequence but entails specific DNA modifications altering gene expression – what are known as epigenetic alterations,” he said.
In the experiments, treatment of the impaired diabetic limbal epithelial cells with the exogenous Wnt-5a accelerated wound healing by 1.4-fold (P < .05), compared with untreated cells and reduced healing time in diabetic organ-ultured corneas by 37% (P < .05).
Treatment with the DNA methylation inhibitor zebularine also increased levels of Wnt-5a in the diabetic limbic epithelial cells by 37% (P < .01), dose-dependently stimulated wound healing by 60% at 24 hours (P < .01), and improved wound healing by 30% in diabetic organ-cultured corneas.
The finding of Wnt-5a as a new diabetic corneal marker regulating wound healing and stem cell function may have implications for other diabetes complications involving impaired wound healing, including diabetic foot ulcers, as they share similar neurovascular, sensory, and immunological compromise with diabetic eye disease, Dr. Shah and colleagues wrote.
“Novel therapies to reverse both types of epigenetic silencing could benefit corneal function and may also prove to be beneficial in other wound healing–related diabetic complications,” they wrote.
The investigators are now working on combination therapies that target both mRNA and DNA methylation in hopes of obtaining even better wound healing.
“Our goal is to develop topical, sustained-release drugs for corneal wound healing,” said Dr. Ljubimov. “Drugs that are [Food and Drug Administration] approved and could be easily applied may be one of the most promising approaches for effective future therapies.”
This work was funded by the National Institutes of Health and the Cedars-Sinai Board of Governors Regenerative Medicine Institute. The authors reported no further disclosures.
A version of this article appeared on Medscape.com.
Vision loss caused by diabetes arises primarily from retinopathy, but up to 70% of people with diabetes also experience corneal problems, including keratopathy and neuropathy. Diabetic keratopathy involves impairments in epithelial wound healing, barrier function, and tear production, along with epithelial erosions and keratitis. As a result, the cornea may heal more slowly and less completely following an injury or procedures such as cataract surgery or laser therapy for diabetic retinopathy.
The abnormal wound healing is caused by impaired limbal epithelial stem cells, and the new research, published online in Diabetologia, involved isolation of those cells from 30 donor eyes of humans with and 23 without diabetes. Significant differences were found in DNA methylation between the cells of those two groups. Specifically, the WNT5A gene was hypermethylated at the promotor region in the diabetic cells and its protein markedly repressed.
However, treatment with various approaches, including exogenous WNT5A methylation inhibitors and a nanoconjugate that inhibits WNT5A suppression, improved corneal epithelial wound healing as well as expression of the limbic epithelial stem cells.
“Overall, [the] Wnt-5a [protein] is a new corneal epithelial wound healing stimulator that can be targeted to improve wound healing and stem cells in the diabetic cornea,” wrote Ruchi Shah, PhD, of the Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, and colleagues.
The finding represents more cellular changes than researchers had previously been aware of, study senior author Alexander Ljubimov, PhD, DSc, director of the eye program at the Institute, said in a statement.
“The discovery does not affect gene sequence but entails specific DNA modifications altering gene expression – what are known as epigenetic alterations,” he said.
In the experiments, treatment of the impaired diabetic limbal epithelial cells with the exogenous Wnt-5a accelerated wound healing by 1.4-fold (P < .05), compared with untreated cells and reduced healing time in diabetic organ-ultured corneas by 37% (P < .05).
Treatment with the DNA methylation inhibitor zebularine also increased levels of Wnt-5a in the diabetic limbic epithelial cells by 37% (P < .01), dose-dependently stimulated wound healing by 60% at 24 hours (P < .01), and improved wound healing by 30% in diabetic organ-cultured corneas.
The finding of Wnt-5a as a new diabetic corneal marker regulating wound healing and stem cell function may have implications for other diabetes complications involving impaired wound healing, including diabetic foot ulcers, as they share similar neurovascular, sensory, and immunological compromise with diabetic eye disease, Dr. Shah and colleagues wrote.
“Novel therapies to reverse both types of epigenetic silencing could benefit corneal function and may also prove to be beneficial in other wound healing–related diabetic complications,” they wrote.
The investigators are now working on combination therapies that target both mRNA and DNA methylation in hopes of obtaining even better wound healing.
“Our goal is to develop topical, sustained-release drugs for corneal wound healing,” said Dr. Ljubimov. “Drugs that are [Food and Drug Administration] approved and could be easily applied may be one of the most promising approaches for effective future therapies.”
This work was funded by the National Institutes of Health and the Cedars-Sinai Board of Governors Regenerative Medicine Institute. The authors reported no further disclosures.
A version of this article appeared on Medscape.com.
FROM DIABETOLOGIA
New guidelines on diabetes-related laboratory testing
The document, titled, “Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus,” is primarily aimed at both laboratory professionals and clinicians involved in diabetes care.
The guidance is focused “on the practical aspects of care in order to assist with decisions regarding the use or interpretation of laboratory tests while screening, diagnosing, or monitoring patients with diabetes,” wrote David B. Sacks, MBChB, chief of the clinical chemistry service at the National Institutes of Health (NIH), Bethesda, Md., and coauthors. It was published online in both Clinical Chemistry and Diabetes Care, including the guidelines and executive summary.
Coauthor M. Sue Kirkman, MD, of the University of North Carolina, Chapel Hill, said in an interview: “One objective of the guidelines is to increase clinicians’ understanding of the strengths and limitations of tests done in a laboratory and also at the point of care, or in daily life, by people with diabetes.”
The evidence-based recommendations, an update of prior versions published in 2011 and 2002, are meant as a supplement to the ADA Standards of Care in Diabetes and do not address aspects of clinical management, she stressed.
Addition of advice on CGM
A significant addition since 2011 is detailed information regarding the use of real-time continuous glucose monitoring (CGM), with a “strong” recommendation based on a “high” level of evidence for use in teens and adults with type 1 diabetes who meet certain criteria, and lower-grade advice to use real-time or intermittently scanned CGM in other populations, including children with diabetes, pregnant women with type 1 diabetes, and adults with type 2 diabetes taking insulin.
The document also reminds clinicians to consider test limitations, Dr. Kirkman pointed out.
“We do a lot of testing in screening, diagnosis, and monitoring of diabetes and its complications, yet for many clinicians we think that any result we get – or that a patient gets from home testing – is perfect. We often don’t think about the accuracy or precision of some tests, things that might interfere with the result, intra-individual variation of the test, or how one test may compare to a test of higher accuracy,” she said.
One example is a recommendation to collect blood samples for glucose analysis in tubes containing a rapidly effective inhibitor of glycolysis such as a granulated citrate buffer. If unavailable, the sample tube should be placed immediately into an ice water slurry and centrifuged within 15-30 minutes to remove the cells.
Without those measures, “red cells in blood sitting in the test tube continue to break down glucose, so the concentration of glucose will start to fall very soon. ... How the specimen is handled makes a huge difference in the result,” Dr. Kirkman emphasized.
Another is the recommendation of a confirmatory test when diagnosing diabetes, regardless of the initial test used (A1c, fasting glucose, or oral glucose tolerance test). “There is large intra-individual variation of fasting glucose and even larger for 2-hour glucose on the oral glucose tolerance test. ... This means if you do the test one week and then repeat it the next day or a week later, the results will be quite different. This is a reason why confirmation of an abnormal test is important. Yet many times this isn’t done,” she noted.
Other “strong” recommendations based on “high” evidence levels include:
- Fasting glucose should be measured in venous plasma when used to establish the diagnosis of diabetes, with a diagnostic cutoff of > 7.0 mmol/L (> 126 mg/dL) for diabetes.
- Frequent blood glucose monitoring is recommended for all people with diabetes treated with intensive insulin regimens (with multiple daily injections or insulin pump therapy) and who are not using CGM.
- Routine use of blood glucose monitoring is not recommended for people with type 2 diabetes who are treated with diet and/or oral agents alone.
- Treatment goals should be based on ADA recommendations, i.e., A1c < 7% (< 53 mmol/mol) if it can be achieved without significant hypoglycemia or other adverse treatment effects, with higher targets for special populations.
- Annual testing for albuminuria should begin in pubertal or postpubertal individuals 5 years after diagnosis of type 1 diabetes and at time of diagnosis of type 2 diabetes, regardless of treatment.
- Urine albumin should be measured annually in adults with diabetes using morning spot urine albumin-to-creatinine ratio.
Other guidance in the document pertains to use of ketone testing, genetic markers, autoimmune markers, and C-peptide.
According to Dr. Sacks, “It’s important to measure accurately, but it’s also very important to communicate the relevance to clinicians and to listen to them and share information. ... Patient care is a team effort.”
Dr. Sachs has reported receiving funding from the NIH. Dr. Kirkman has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The document, titled, “Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus,” is primarily aimed at both laboratory professionals and clinicians involved in diabetes care.
The guidance is focused “on the practical aspects of care in order to assist with decisions regarding the use or interpretation of laboratory tests while screening, diagnosing, or monitoring patients with diabetes,” wrote David B. Sacks, MBChB, chief of the clinical chemistry service at the National Institutes of Health (NIH), Bethesda, Md., and coauthors. It was published online in both Clinical Chemistry and Diabetes Care, including the guidelines and executive summary.
Coauthor M. Sue Kirkman, MD, of the University of North Carolina, Chapel Hill, said in an interview: “One objective of the guidelines is to increase clinicians’ understanding of the strengths and limitations of tests done in a laboratory and also at the point of care, or in daily life, by people with diabetes.”
The evidence-based recommendations, an update of prior versions published in 2011 and 2002, are meant as a supplement to the ADA Standards of Care in Diabetes and do not address aspects of clinical management, she stressed.
Addition of advice on CGM
A significant addition since 2011 is detailed information regarding the use of real-time continuous glucose monitoring (CGM), with a “strong” recommendation based on a “high” level of evidence for use in teens and adults with type 1 diabetes who meet certain criteria, and lower-grade advice to use real-time or intermittently scanned CGM in other populations, including children with diabetes, pregnant women with type 1 diabetes, and adults with type 2 diabetes taking insulin.
The document also reminds clinicians to consider test limitations, Dr. Kirkman pointed out.
“We do a lot of testing in screening, diagnosis, and monitoring of diabetes and its complications, yet for many clinicians we think that any result we get – or that a patient gets from home testing – is perfect. We often don’t think about the accuracy or precision of some tests, things that might interfere with the result, intra-individual variation of the test, or how one test may compare to a test of higher accuracy,” she said.
One example is a recommendation to collect blood samples for glucose analysis in tubes containing a rapidly effective inhibitor of glycolysis such as a granulated citrate buffer. If unavailable, the sample tube should be placed immediately into an ice water slurry and centrifuged within 15-30 minutes to remove the cells.
Without those measures, “red cells in blood sitting in the test tube continue to break down glucose, so the concentration of glucose will start to fall very soon. ... How the specimen is handled makes a huge difference in the result,” Dr. Kirkman emphasized.
Another is the recommendation of a confirmatory test when diagnosing diabetes, regardless of the initial test used (A1c, fasting glucose, or oral glucose tolerance test). “There is large intra-individual variation of fasting glucose and even larger for 2-hour glucose on the oral glucose tolerance test. ... This means if you do the test one week and then repeat it the next day or a week later, the results will be quite different. This is a reason why confirmation of an abnormal test is important. Yet many times this isn’t done,” she noted.
Other “strong” recommendations based on “high” evidence levels include:
- Fasting glucose should be measured in venous plasma when used to establish the diagnosis of diabetes, with a diagnostic cutoff of > 7.0 mmol/L (> 126 mg/dL) for diabetes.
- Frequent blood glucose monitoring is recommended for all people with diabetes treated with intensive insulin regimens (with multiple daily injections or insulin pump therapy) and who are not using CGM.
- Routine use of blood glucose monitoring is not recommended for people with type 2 diabetes who are treated with diet and/or oral agents alone.
- Treatment goals should be based on ADA recommendations, i.e., A1c < 7% (< 53 mmol/mol) if it can be achieved without significant hypoglycemia or other adverse treatment effects, with higher targets for special populations.
- Annual testing for albuminuria should begin in pubertal or postpubertal individuals 5 years after diagnosis of type 1 diabetes and at time of diagnosis of type 2 diabetes, regardless of treatment.
- Urine albumin should be measured annually in adults with diabetes using morning spot urine albumin-to-creatinine ratio.
Other guidance in the document pertains to use of ketone testing, genetic markers, autoimmune markers, and C-peptide.
According to Dr. Sacks, “It’s important to measure accurately, but it’s also very important to communicate the relevance to clinicians and to listen to them and share information. ... Patient care is a team effort.”
Dr. Sachs has reported receiving funding from the NIH. Dr. Kirkman has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The document, titled, “Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus,” is primarily aimed at both laboratory professionals and clinicians involved in diabetes care.
The guidance is focused “on the practical aspects of care in order to assist with decisions regarding the use or interpretation of laboratory tests while screening, diagnosing, or monitoring patients with diabetes,” wrote David B. Sacks, MBChB, chief of the clinical chemistry service at the National Institutes of Health (NIH), Bethesda, Md., and coauthors. It was published online in both Clinical Chemistry and Diabetes Care, including the guidelines and executive summary.
Coauthor M. Sue Kirkman, MD, of the University of North Carolina, Chapel Hill, said in an interview: “One objective of the guidelines is to increase clinicians’ understanding of the strengths and limitations of tests done in a laboratory and also at the point of care, or in daily life, by people with diabetes.”
The evidence-based recommendations, an update of prior versions published in 2011 and 2002, are meant as a supplement to the ADA Standards of Care in Diabetes and do not address aspects of clinical management, she stressed.
Addition of advice on CGM
A significant addition since 2011 is detailed information regarding the use of real-time continuous glucose monitoring (CGM), with a “strong” recommendation based on a “high” level of evidence for use in teens and adults with type 1 diabetes who meet certain criteria, and lower-grade advice to use real-time or intermittently scanned CGM in other populations, including children with diabetes, pregnant women with type 1 diabetes, and adults with type 2 diabetes taking insulin.
The document also reminds clinicians to consider test limitations, Dr. Kirkman pointed out.
“We do a lot of testing in screening, diagnosis, and monitoring of diabetes and its complications, yet for many clinicians we think that any result we get – or that a patient gets from home testing – is perfect. We often don’t think about the accuracy or precision of some tests, things that might interfere with the result, intra-individual variation of the test, or how one test may compare to a test of higher accuracy,” she said.
One example is a recommendation to collect blood samples for glucose analysis in tubes containing a rapidly effective inhibitor of glycolysis such as a granulated citrate buffer. If unavailable, the sample tube should be placed immediately into an ice water slurry and centrifuged within 15-30 minutes to remove the cells.
Without those measures, “red cells in blood sitting in the test tube continue to break down glucose, so the concentration of glucose will start to fall very soon. ... How the specimen is handled makes a huge difference in the result,” Dr. Kirkman emphasized.
Another is the recommendation of a confirmatory test when diagnosing diabetes, regardless of the initial test used (A1c, fasting glucose, or oral glucose tolerance test). “There is large intra-individual variation of fasting glucose and even larger for 2-hour glucose on the oral glucose tolerance test. ... This means if you do the test one week and then repeat it the next day or a week later, the results will be quite different. This is a reason why confirmation of an abnormal test is important. Yet many times this isn’t done,” she noted.
Other “strong” recommendations based on “high” evidence levels include:
- Fasting glucose should be measured in venous plasma when used to establish the diagnosis of diabetes, with a diagnostic cutoff of > 7.0 mmol/L (> 126 mg/dL) for diabetes.
- Frequent blood glucose monitoring is recommended for all people with diabetes treated with intensive insulin regimens (with multiple daily injections or insulin pump therapy) and who are not using CGM.
- Routine use of blood glucose monitoring is not recommended for people with type 2 diabetes who are treated with diet and/or oral agents alone.
- Treatment goals should be based on ADA recommendations, i.e., A1c < 7% (< 53 mmol/mol) if it can be achieved without significant hypoglycemia or other adverse treatment effects, with higher targets for special populations.
- Annual testing for albuminuria should begin in pubertal or postpubertal individuals 5 years after diagnosis of type 1 diabetes and at time of diagnosis of type 2 diabetes, regardless of treatment.
- Urine albumin should be measured annually in adults with diabetes using morning spot urine albumin-to-creatinine ratio.
Other guidance in the document pertains to use of ketone testing, genetic markers, autoimmune markers, and C-peptide.
According to Dr. Sacks, “It’s important to measure accurately, but it’s also very important to communicate the relevance to clinicians and to listen to them and share information. ... Patient care is a team effort.”
Dr. Sachs has reported receiving funding from the NIH. Dr. Kirkman has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM CLINICAL CHEMISTRY AND DIABETES CARE
Debate: Initial combination therapy for type 2 diabetes?
SAN DIEGO –
This question was debated by two well-known clinician-researchers in the diabetes world at the recent annual scientific sessions of the American Diabetes Association.
Ralph A. DeFronzo, MD, argued for combination therapy at the time of diagnosis, and David M. Nathan, MD, countered that sequential therapy is a better way to go.
‘The ominous octet’: Addressing multiple underlying defects
Of course, Dr. DeFronzo said, the right agents must be selected. “The drugs we’re going to use as combination at a minimum have to correct the underlying insulin resistance and beta-cell failure, or we are not going to be successful.”
In addition, he said, these drugs should also provide protection against cardiovascular, kidney, and fatty liver disease, because “[managing] diabetes is more than just controlling the glucose.”
Recent U.S. data suggest that half of people with diabetes have a hemoglobin A1c above 7%, and a quarter remain above 8%. “We’re not really doing a very good job in terms of glycemic control,” said Dr. DeFronzo, chief of the diabetes division at University of Texas, San Antonio.
One reason for this failure, he said, is the complex pathophysiology of type 2 diabetes represented by eight major defects, what he called the “ominous octet”: decreased pancreatic insulin secretion, gut incretin effects, glucose uptake in the muscle, increased lipolysis, glucose reabsorption in the kidney, hepatic glucose production, increased glucagon secretion, and neurotransmitter dysfunction.
“There are eight problems, so you’re going to need multiple drugs in combination ... not ones that just lower the A1c.”
And, Dr. DeFronzo said, these drugs “must be started early in the natural history of type 2 diabetes if progressive beta-cell failure is to be prevented.”
He pointed to the United Kingdom Prospective Diabetes Study (UKPDS), in which the sulfonylurea glyburide was used first, followed by metformin. With each drug, the A1c decreased initially but then rose within 3 years. By 15 years, 65% of participants were taking insulin.
More recently, the GRADE study examined the effects of adding four different glucose-lowering agents (glimepiride, sitagliptin, liraglutide, or insulin glargine) in people who hadn’t achieved target A1c with metformin.
“So, by definition, drug number one failed,” he observed.
During the study, all participants showed an initial A1c drop, followed by progressive failure, “again ... showing that stepwise therapy doesn’t work.”
All patients with type 2 diabetes at his center are treated using the “DeFronzo algorithm” consisting of three drug classes: a glucagon-like peptide-1 (GLP-1) agonist, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, and pioglitazone, as each of them targets more than one of the “ominous octet” defects.
“The drugs that clearly do not work on a long-term basis are metformin and sulfonylureas,” he emphasized.
Several studies demonstrate the efficacy of combination therapy, he said. In one, DURATION 8, the combination of exenatide and dapagliflozin was superior to either agent individually in lowering A1c, cardiovascular events, and all-cause mortality over 2 years.
And in the 5-year VERIFY study, early combination therapy with vildagliptin plus metformin proved superior in A1c-lowering to starting patients on metformin and adding vildagliptin later.
Dr. DeFronzo’s own “knock-out punch” study, EDICT, in people with new-onset type 2 diabetes, compared the initial combination of metformin, pioglitazone, and exenatide with conventional sequential add-on therapy with metformin, glipizide, and insulin glargine.
The primary endpoint – the difference in the proportion of patients with A1c less than 6.5% – was 70% versus 29% with combination compared with sequential therapy, a difference “as robust as you can be going against the stepwise approach” at P < .00001, he said.
The combination therapy virtually normalized both insulin sensitivity and beta-cell function, whereas the conventional therapy did neither.
Also from Dr. DeFronzo’s group, in the Qatar study, which compared exenatide plus pioglitazone with basal-bolus insulin in people with about 10 years’ duration of type 2 diabetes and A1c above 7.5% taking sulfonylurea plus metformin, the combination therapy produced an A1c of 6.2% versus 7.1% with insulin.
Dr. DeFronzo pointed to new language added to the ADA Standards of Medical Care in Diabetes in 2022.
While still endorsing stepwise therapy, the document also says that “there are data to support initial combination therapy for more rapid attainment of glycemic targets and longer durability of glycemic effect.” The two references cited are EDICT and VERIFY.
“Finally, the American Diabetes Association has gotten the message,” he concluded.
Sequential therapy: Far more data, lower cost
Dr. Nathan began by pointing out that the ADA Standards of Care continue to advise use of metformin as first-line therapy for type 2 diabetes “because of its high efficacy in lowering A1c, minimal hypoglycemia risk when used as monotherapy, weight neutrality with the potential for modest weight loss, good safety profile, and low cost.”
He emphasized that he was not arguing “against the use of early or even initial combination therapy when there are co-existent morbidities [such as cardiovascular or chronic kidney disease] that merit use of demonstrably effective medications.” But Dr. Nathan pointed out, those patients are not the majority with type 2 diabetes.
He laid out four main arguments for choosing traditional sequential therapy over initial combination therapy. For one, it “enables determination of efficacy of adding individual medications, while initial combination precludes determining benefits of individual drugs.”
Second, traditional sequential therapy allows for assessment of side effects from individual drugs.
“With Dr. DeFronzo’s algorithm you throw everything at them, and if they get nausea, vomiting, or diarrhea, you won’t know which drug it is ... If they get an allergic reaction, you won’t know which medication it is,” observed Dr. Nathan, who is director of the clinical research center and the diabetes center at Massachusetts General Hospital, Boston.
Moreover, he said, traditional sequential therapy “promotes individualization, with selection of drugs, which is something we’re laboring to achieve. Initial combination obviously limits that.”
Further, sequential therapy is “parsimonious and cost-effective, whereas initial combination therapy is expensive, with modest advantages at most.”
And, there are “lots of data” supporting traditional sequential therapy and relatively little for initial combination therapy.
Dr. Nathan added that when he searched the literature for relevant randomized clinical trials, he found 16 investigating initial combination therapy versus monotherapy, but only three that examined combination versus sequential therapy.
“Very few of them, except for EDICT and VERIFY, actually include the sequential therapy that we would use in practice,” he said.
Moreover, he observed, except for the VERIFY study, most are less than half a year in duration. And in VERIFY, there was an initial 20% difference in the proportions of patients with A1c below 7.0%, but by 12 months, that difference had shrunk to just 5%-6%.
“So, looking over time is very important,” Dr. Nathan cautioned. “We really have to be careful ... Six months is barely enough time to see A1c equilibrate ... You really need to study a long-term, chronic, progressive disease like type 2 diabetes over a long enough period of time to be clinically meaningful.”
Dr. Nathan acknowledged to Dr. DeFronzo that the latter’s EDICT study was “well conducted” and “long enough,” and that the researchers did examine monotherapy versus sequential therapy. However, he pointed out that it was a small study with 249 patients and the dropout rate was high, with 58% of patients remaining in the study with triple therapy versus 68% for conventional treatment. “That’s a bit problematic,” Dr. Nathan noted.
At 2 years, the “trivial” difference in A1c was 6.5% with conventional therapy versus 6.0% with triple therapy. “This is all on the very flat complications curve with regard to A1c,” he observed.
Patients treated with sequential therapy with sulfonylurea and insulin had higher rates of hypoglycemia and weight gain, whereas the combination triple therapy group had more gastrointestinal side effects and edema.
However, the most dramatic difference was cost: the average wholesale price for sequential therapy totaled about $85 per month, compared with $1,310 for initial combination therapy. For the approximately 1.5 million patients with new-onset type 2 diabetes in the United States, that difference comes to an additional cost per year of about $22 billion, Dr. Nathan calculated.
“Although current sequential therapy leaves much to be desired ... initial combination therapy has generally only been tested for brief, clinically insufficient periods.
“And therefore, I think sequential therapy is still what is called for,” he concluded. “Well-powered, acceptable-duration studies need to be performed before we can adopt initial/early combination therapy as the standard of care.”
Dr. DeFronzo has reported receiving research support from Boehringer Ingelheim, AstraZeneca, and Merck; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca; and participation on a data safety monitoring board or advisory board for AstraZeneca, Intarcia, Novo Nordisk, and Boehringer Ingelheim. Dr. Nathan has reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
SAN DIEGO –
This question was debated by two well-known clinician-researchers in the diabetes world at the recent annual scientific sessions of the American Diabetes Association.
Ralph A. DeFronzo, MD, argued for combination therapy at the time of diagnosis, and David M. Nathan, MD, countered that sequential therapy is a better way to go.
‘The ominous octet’: Addressing multiple underlying defects
Of course, Dr. DeFronzo said, the right agents must be selected. “The drugs we’re going to use as combination at a minimum have to correct the underlying insulin resistance and beta-cell failure, or we are not going to be successful.”
In addition, he said, these drugs should also provide protection against cardiovascular, kidney, and fatty liver disease, because “[managing] diabetes is more than just controlling the glucose.”
Recent U.S. data suggest that half of people with diabetes have a hemoglobin A1c above 7%, and a quarter remain above 8%. “We’re not really doing a very good job in terms of glycemic control,” said Dr. DeFronzo, chief of the diabetes division at University of Texas, San Antonio.
One reason for this failure, he said, is the complex pathophysiology of type 2 diabetes represented by eight major defects, what he called the “ominous octet”: decreased pancreatic insulin secretion, gut incretin effects, glucose uptake in the muscle, increased lipolysis, glucose reabsorption in the kidney, hepatic glucose production, increased glucagon secretion, and neurotransmitter dysfunction.
“There are eight problems, so you’re going to need multiple drugs in combination ... not ones that just lower the A1c.”
And, Dr. DeFronzo said, these drugs “must be started early in the natural history of type 2 diabetes if progressive beta-cell failure is to be prevented.”
He pointed to the United Kingdom Prospective Diabetes Study (UKPDS), in which the sulfonylurea glyburide was used first, followed by metformin. With each drug, the A1c decreased initially but then rose within 3 years. By 15 years, 65% of participants were taking insulin.
More recently, the GRADE study examined the effects of adding four different glucose-lowering agents (glimepiride, sitagliptin, liraglutide, or insulin glargine) in people who hadn’t achieved target A1c with metformin.
“So, by definition, drug number one failed,” he observed.
During the study, all participants showed an initial A1c drop, followed by progressive failure, “again ... showing that stepwise therapy doesn’t work.”
All patients with type 2 diabetes at his center are treated using the “DeFronzo algorithm” consisting of three drug classes: a glucagon-like peptide-1 (GLP-1) agonist, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, and pioglitazone, as each of them targets more than one of the “ominous octet” defects.
“The drugs that clearly do not work on a long-term basis are metformin and sulfonylureas,” he emphasized.
Several studies demonstrate the efficacy of combination therapy, he said. In one, DURATION 8, the combination of exenatide and dapagliflozin was superior to either agent individually in lowering A1c, cardiovascular events, and all-cause mortality over 2 years.
And in the 5-year VERIFY study, early combination therapy with vildagliptin plus metformin proved superior in A1c-lowering to starting patients on metformin and adding vildagliptin later.
Dr. DeFronzo’s own “knock-out punch” study, EDICT, in people with new-onset type 2 diabetes, compared the initial combination of metformin, pioglitazone, and exenatide with conventional sequential add-on therapy with metformin, glipizide, and insulin glargine.
The primary endpoint – the difference in the proportion of patients with A1c less than 6.5% – was 70% versus 29% with combination compared with sequential therapy, a difference “as robust as you can be going against the stepwise approach” at P < .00001, he said.
The combination therapy virtually normalized both insulin sensitivity and beta-cell function, whereas the conventional therapy did neither.
Also from Dr. DeFronzo’s group, in the Qatar study, which compared exenatide plus pioglitazone with basal-bolus insulin in people with about 10 years’ duration of type 2 diabetes and A1c above 7.5% taking sulfonylurea plus metformin, the combination therapy produced an A1c of 6.2% versus 7.1% with insulin.
Dr. DeFronzo pointed to new language added to the ADA Standards of Medical Care in Diabetes in 2022.
While still endorsing stepwise therapy, the document also says that “there are data to support initial combination therapy for more rapid attainment of glycemic targets and longer durability of glycemic effect.” The two references cited are EDICT and VERIFY.
“Finally, the American Diabetes Association has gotten the message,” he concluded.
Sequential therapy: Far more data, lower cost
Dr. Nathan began by pointing out that the ADA Standards of Care continue to advise use of metformin as first-line therapy for type 2 diabetes “because of its high efficacy in lowering A1c, minimal hypoglycemia risk when used as monotherapy, weight neutrality with the potential for modest weight loss, good safety profile, and low cost.”
He emphasized that he was not arguing “against the use of early or even initial combination therapy when there are co-existent morbidities [such as cardiovascular or chronic kidney disease] that merit use of demonstrably effective medications.” But Dr. Nathan pointed out, those patients are not the majority with type 2 diabetes.
He laid out four main arguments for choosing traditional sequential therapy over initial combination therapy. For one, it “enables determination of efficacy of adding individual medications, while initial combination precludes determining benefits of individual drugs.”
Second, traditional sequential therapy allows for assessment of side effects from individual drugs.
“With Dr. DeFronzo’s algorithm you throw everything at them, and if they get nausea, vomiting, or diarrhea, you won’t know which drug it is ... If they get an allergic reaction, you won’t know which medication it is,” observed Dr. Nathan, who is director of the clinical research center and the diabetes center at Massachusetts General Hospital, Boston.
Moreover, he said, traditional sequential therapy “promotes individualization, with selection of drugs, which is something we’re laboring to achieve. Initial combination obviously limits that.”
Further, sequential therapy is “parsimonious and cost-effective, whereas initial combination therapy is expensive, with modest advantages at most.”
And, there are “lots of data” supporting traditional sequential therapy and relatively little for initial combination therapy.
Dr. Nathan added that when he searched the literature for relevant randomized clinical trials, he found 16 investigating initial combination therapy versus monotherapy, but only three that examined combination versus sequential therapy.
“Very few of them, except for EDICT and VERIFY, actually include the sequential therapy that we would use in practice,” he said.
Moreover, he observed, except for the VERIFY study, most are less than half a year in duration. And in VERIFY, there was an initial 20% difference in the proportions of patients with A1c below 7.0%, but by 12 months, that difference had shrunk to just 5%-6%.
“So, looking over time is very important,” Dr. Nathan cautioned. “We really have to be careful ... Six months is barely enough time to see A1c equilibrate ... You really need to study a long-term, chronic, progressive disease like type 2 diabetes over a long enough period of time to be clinically meaningful.”
Dr. Nathan acknowledged to Dr. DeFronzo that the latter’s EDICT study was “well conducted” and “long enough,” and that the researchers did examine monotherapy versus sequential therapy. However, he pointed out that it was a small study with 249 patients and the dropout rate was high, with 58% of patients remaining in the study with triple therapy versus 68% for conventional treatment. “That’s a bit problematic,” Dr. Nathan noted.
At 2 years, the “trivial” difference in A1c was 6.5% with conventional therapy versus 6.0% with triple therapy. “This is all on the very flat complications curve with regard to A1c,” he observed.
Patients treated with sequential therapy with sulfonylurea and insulin had higher rates of hypoglycemia and weight gain, whereas the combination triple therapy group had more gastrointestinal side effects and edema.
However, the most dramatic difference was cost: the average wholesale price for sequential therapy totaled about $85 per month, compared with $1,310 for initial combination therapy. For the approximately 1.5 million patients with new-onset type 2 diabetes in the United States, that difference comes to an additional cost per year of about $22 billion, Dr. Nathan calculated.
“Although current sequential therapy leaves much to be desired ... initial combination therapy has generally only been tested for brief, clinically insufficient periods.
“And therefore, I think sequential therapy is still what is called for,” he concluded. “Well-powered, acceptable-duration studies need to be performed before we can adopt initial/early combination therapy as the standard of care.”
Dr. DeFronzo has reported receiving research support from Boehringer Ingelheim, AstraZeneca, and Merck; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca; and participation on a data safety monitoring board or advisory board for AstraZeneca, Intarcia, Novo Nordisk, and Boehringer Ingelheim. Dr. Nathan has reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
SAN DIEGO –
This question was debated by two well-known clinician-researchers in the diabetes world at the recent annual scientific sessions of the American Diabetes Association.
Ralph A. DeFronzo, MD, argued for combination therapy at the time of diagnosis, and David M. Nathan, MD, countered that sequential therapy is a better way to go.
‘The ominous octet’: Addressing multiple underlying defects
Of course, Dr. DeFronzo said, the right agents must be selected. “The drugs we’re going to use as combination at a minimum have to correct the underlying insulin resistance and beta-cell failure, or we are not going to be successful.”
In addition, he said, these drugs should also provide protection against cardiovascular, kidney, and fatty liver disease, because “[managing] diabetes is more than just controlling the glucose.”
Recent U.S. data suggest that half of people with diabetes have a hemoglobin A1c above 7%, and a quarter remain above 8%. “We’re not really doing a very good job in terms of glycemic control,” said Dr. DeFronzo, chief of the diabetes division at University of Texas, San Antonio.
One reason for this failure, he said, is the complex pathophysiology of type 2 diabetes represented by eight major defects, what he called the “ominous octet”: decreased pancreatic insulin secretion, gut incretin effects, glucose uptake in the muscle, increased lipolysis, glucose reabsorption in the kidney, hepatic glucose production, increased glucagon secretion, and neurotransmitter dysfunction.
“There are eight problems, so you’re going to need multiple drugs in combination ... not ones that just lower the A1c.”
And, Dr. DeFronzo said, these drugs “must be started early in the natural history of type 2 diabetes if progressive beta-cell failure is to be prevented.”
He pointed to the United Kingdom Prospective Diabetes Study (UKPDS), in which the sulfonylurea glyburide was used first, followed by metformin. With each drug, the A1c decreased initially but then rose within 3 years. By 15 years, 65% of participants were taking insulin.
More recently, the GRADE study examined the effects of adding four different glucose-lowering agents (glimepiride, sitagliptin, liraglutide, or insulin glargine) in people who hadn’t achieved target A1c with metformin.
“So, by definition, drug number one failed,” he observed.
During the study, all participants showed an initial A1c drop, followed by progressive failure, “again ... showing that stepwise therapy doesn’t work.”
All patients with type 2 diabetes at his center are treated using the “DeFronzo algorithm” consisting of three drug classes: a glucagon-like peptide-1 (GLP-1) agonist, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, and pioglitazone, as each of them targets more than one of the “ominous octet” defects.
“The drugs that clearly do not work on a long-term basis are metformin and sulfonylureas,” he emphasized.
Several studies demonstrate the efficacy of combination therapy, he said. In one, DURATION 8, the combination of exenatide and dapagliflozin was superior to either agent individually in lowering A1c, cardiovascular events, and all-cause mortality over 2 years.
And in the 5-year VERIFY study, early combination therapy with vildagliptin plus metformin proved superior in A1c-lowering to starting patients on metformin and adding vildagliptin later.
Dr. DeFronzo’s own “knock-out punch” study, EDICT, in people with new-onset type 2 diabetes, compared the initial combination of metformin, pioglitazone, and exenatide with conventional sequential add-on therapy with metformin, glipizide, and insulin glargine.
The primary endpoint – the difference in the proportion of patients with A1c less than 6.5% – was 70% versus 29% with combination compared with sequential therapy, a difference “as robust as you can be going against the stepwise approach” at P < .00001, he said.
The combination therapy virtually normalized both insulin sensitivity and beta-cell function, whereas the conventional therapy did neither.
Also from Dr. DeFronzo’s group, in the Qatar study, which compared exenatide plus pioglitazone with basal-bolus insulin in people with about 10 years’ duration of type 2 diabetes and A1c above 7.5% taking sulfonylurea plus metformin, the combination therapy produced an A1c of 6.2% versus 7.1% with insulin.
Dr. DeFronzo pointed to new language added to the ADA Standards of Medical Care in Diabetes in 2022.
While still endorsing stepwise therapy, the document also says that “there are data to support initial combination therapy for more rapid attainment of glycemic targets and longer durability of glycemic effect.” The two references cited are EDICT and VERIFY.
“Finally, the American Diabetes Association has gotten the message,” he concluded.
Sequential therapy: Far more data, lower cost
Dr. Nathan began by pointing out that the ADA Standards of Care continue to advise use of metformin as first-line therapy for type 2 diabetes “because of its high efficacy in lowering A1c, minimal hypoglycemia risk when used as monotherapy, weight neutrality with the potential for modest weight loss, good safety profile, and low cost.”
He emphasized that he was not arguing “against the use of early or even initial combination therapy when there are co-existent morbidities [such as cardiovascular or chronic kidney disease] that merit use of demonstrably effective medications.” But Dr. Nathan pointed out, those patients are not the majority with type 2 diabetes.
He laid out four main arguments for choosing traditional sequential therapy over initial combination therapy. For one, it “enables determination of efficacy of adding individual medications, while initial combination precludes determining benefits of individual drugs.”
Second, traditional sequential therapy allows for assessment of side effects from individual drugs.
“With Dr. DeFronzo’s algorithm you throw everything at them, and if they get nausea, vomiting, or diarrhea, you won’t know which drug it is ... If they get an allergic reaction, you won’t know which medication it is,” observed Dr. Nathan, who is director of the clinical research center and the diabetes center at Massachusetts General Hospital, Boston.
Moreover, he said, traditional sequential therapy “promotes individualization, with selection of drugs, which is something we’re laboring to achieve. Initial combination obviously limits that.”
Further, sequential therapy is “parsimonious and cost-effective, whereas initial combination therapy is expensive, with modest advantages at most.”
And, there are “lots of data” supporting traditional sequential therapy and relatively little for initial combination therapy.
Dr. Nathan added that when he searched the literature for relevant randomized clinical trials, he found 16 investigating initial combination therapy versus monotherapy, but only three that examined combination versus sequential therapy.
“Very few of them, except for EDICT and VERIFY, actually include the sequential therapy that we would use in practice,” he said.
Moreover, he observed, except for the VERIFY study, most are less than half a year in duration. And in VERIFY, there was an initial 20% difference in the proportions of patients with A1c below 7.0%, but by 12 months, that difference had shrunk to just 5%-6%.
“So, looking over time is very important,” Dr. Nathan cautioned. “We really have to be careful ... Six months is barely enough time to see A1c equilibrate ... You really need to study a long-term, chronic, progressive disease like type 2 diabetes over a long enough period of time to be clinically meaningful.”
Dr. Nathan acknowledged to Dr. DeFronzo that the latter’s EDICT study was “well conducted” and “long enough,” and that the researchers did examine monotherapy versus sequential therapy. However, he pointed out that it was a small study with 249 patients and the dropout rate was high, with 58% of patients remaining in the study with triple therapy versus 68% for conventional treatment. “That’s a bit problematic,” Dr. Nathan noted.
At 2 years, the “trivial” difference in A1c was 6.5% with conventional therapy versus 6.0% with triple therapy. “This is all on the very flat complications curve with regard to A1c,” he observed.
Patients treated with sequential therapy with sulfonylurea and insulin had higher rates of hypoglycemia and weight gain, whereas the combination triple therapy group had more gastrointestinal side effects and edema.
However, the most dramatic difference was cost: the average wholesale price for sequential therapy totaled about $85 per month, compared with $1,310 for initial combination therapy. For the approximately 1.5 million patients with new-onset type 2 diabetes in the United States, that difference comes to an additional cost per year of about $22 billion, Dr. Nathan calculated.
“Although current sequential therapy leaves much to be desired ... initial combination therapy has generally only been tested for brief, clinically insufficient periods.
“And therefore, I think sequential therapy is still what is called for,” he concluded. “Well-powered, acceptable-duration studies need to be performed before we can adopt initial/early combination therapy as the standard of care.”
Dr. DeFronzo has reported receiving research support from Boehringer Ingelheim, AstraZeneca, and Merck; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca; and participation on a data safety monitoring board or advisory board for AstraZeneca, Intarcia, Novo Nordisk, and Boehringer Ingelheim. Dr. Nathan has reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
FDA clears the Tandem Mobi insulin pump
The product is half the size of the company’s t:slim X2 and is now the smallest of the commercially available durable tubed pumps. It is fully controllable from a mobile app through a user’s compatible iPhone.
Features of the Mobi include a 200-unit insulin cartridge and an on-pump button that can be used instead of the phone for bolusing insulin. The device can be clipped to clothing or worn on-body with an adhesive sleeve that is sold separately.
The Mobi is compatible with all existing Tandem-branded infusion sets manufactured by the Convatec Group, and there is a new 5-inch tubing option made just for the Tandem Mobi.
The Mobi is part of a hybrid-closed loop automated delivery system, along with the current Control-IQ technology and a compatible continuous glucose monitor (CGM). The CGM sensor predicts glucose values 30 minutes ahead and adjusts insulin delivery every 5 minutes to prevent highs and lows. Users must still manually bolus for meals. The system can deliver automatic correction boluses for up to 1 hour to prevent hyperglycemia.
Limited release of the Tandem Mobi is expected in late 2023, followed by full commercial availability in early 2024.
A version of this article originally appeared on Medscape.com.
The product is half the size of the company’s t:slim X2 and is now the smallest of the commercially available durable tubed pumps. It is fully controllable from a mobile app through a user’s compatible iPhone.
Features of the Mobi include a 200-unit insulin cartridge and an on-pump button that can be used instead of the phone for bolusing insulin. The device can be clipped to clothing or worn on-body with an adhesive sleeve that is sold separately.
The Mobi is compatible with all existing Tandem-branded infusion sets manufactured by the Convatec Group, and there is a new 5-inch tubing option made just for the Tandem Mobi.
The Mobi is part of a hybrid-closed loop automated delivery system, along with the current Control-IQ technology and a compatible continuous glucose monitor (CGM). The CGM sensor predicts glucose values 30 minutes ahead and adjusts insulin delivery every 5 minutes to prevent highs and lows. Users must still manually bolus for meals. The system can deliver automatic correction boluses for up to 1 hour to prevent hyperglycemia.
Limited release of the Tandem Mobi is expected in late 2023, followed by full commercial availability in early 2024.
A version of this article originally appeared on Medscape.com.
The product is half the size of the company’s t:slim X2 and is now the smallest of the commercially available durable tubed pumps. It is fully controllable from a mobile app through a user’s compatible iPhone.
Features of the Mobi include a 200-unit insulin cartridge and an on-pump button that can be used instead of the phone for bolusing insulin. The device can be clipped to clothing or worn on-body with an adhesive sleeve that is sold separately.
The Mobi is compatible with all existing Tandem-branded infusion sets manufactured by the Convatec Group, and there is a new 5-inch tubing option made just for the Tandem Mobi.
The Mobi is part of a hybrid-closed loop automated delivery system, along with the current Control-IQ technology and a compatible continuous glucose monitor (CGM). The CGM sensor predicts glucose values 30 minutes ahead and adjusts insulin delivery every 5 minutes to prevent highs and lows. Users must still manually bolus for meals. The system can deliver automatic correction boluses for up to 1 hour to prevent hyperglycemia.
Limited release of the Tandem Mobi is expected in late 2023, followed by full commercial availability in early 2024.
A version of this article originally appeared on Medscape.com.
Aging and type 1 diabetes: ‘Complete picture’ 40 years on
SAN DIEGO –
New funding for 2022-2027 for the DCCT long-term observational follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC) will go toward investigating aspects of type 1 diabetes that are associated with aging and are also common in type 2 diabetes, including cardiovascular disease, fatty liver disease, and sleep apnea.
The original randomized DCCT clinical trial results, published in 1993 in the New England Journal of Medicine, proved that early intensive glycemic control was the key to preventing or slowing the progression of long-term eye, kidney, and nerve complications of type 1 diabetes. Subsequently, EDIC has yielded many more major findings including that early tight glycemic control also reduces cardiovascular risk and prolongs survival in type 1 diabetes.
And although the phenomenon of metabolic memory initially seen in EDIC means that early glycemic control is important, subsequent EDIC data also have suggested that it is never too late to initiate intensive glycemic control, speakers emphasized during a special symposium commemorating 40 years since the start of DCCT, held during the annual scientific sessions of the American Diabetes Association. As with the 30-year DCCT/EDIC commemorative symposium held in 2013, local study participants were in the audience and were acknowledged with long applause.
Together, DCCT and EDIC – both funded by the National Institutes of Health at 27 sites in the United States and Canada – have changed the standard of care for people with type 1 diabetes and continue to inform clinical practice. Prior to the DCCT, between 1930 and 1970, about a third of people with type 1 diabetes developed vision loss and one in five experienced kidney failure and/or myocardial infarction. Stroke and amputation were also common, DCCT/EDIC chair David M. Nathan, MD, said while introducing the symposium.
“All of the advances in care of type 1 diabetes have developed because this study demonstrated that it was important – continuous glucose monitoring (CGM), new insulins, better [insulin] pumps. ... I think the most profound finding is that mortality in our intensively treated cohort is the same as in the general population. That says it all,” Dr. Nathan said in an interview.
And now, “what we still have yet to contribute is what happens to type 1 diabetes as people get older,” added Dr. Nathan, a professor of medicine at Harvard Medical School and director of the Diabetes Center at Massachusetts General Hospital, both in Boston.
‘Something that heretofore none of us could have imagined’
The 1,441 DCCT participants had a mean age of 27 years at baseline in 1983, when they were randomized to intensive insulin therapy or usual care. The 1,375 participants (96%) who continued into EDIC in 1994 were an average of 35 years old at that point, when the usual care group was taught intensive glycemic management and all participants returned to their personal health care teams. The 1,075 participants in EDIC today are an average age of 63 years.
Only 11 participants had died at the start of EDIC, and just 250 (17%) have died as of 2023, said study coordinator cochair Gayle Lorenzi, RN, who is a certified diabetes care and education specialist at the University of California, San Diego.
“DCCT/EDIC because of its longevity represents a unique opportunity to explore aging in long duration of type 1 diabetes, something that heretofore none of us could have imagined, especially for those of you in the audience who started your careers in the 70s and 80s,” Ms. Lorenzi commented.
About 36% of the cohort now has overweight and 40% have obesity, mirroring the general population. And they now have a mean hemoglobin A1c of 7.3%.
According to Barbara H. Braffett, PhD, co–principal investigator at the DCCT/EDIC data coordinating center: “The EDIC study is now shifting its focus during the next 5 years to understand the clinical course of type 1 diabetes in the setting of advancing duration and age, as well as increasing adiposity, which has progressively affected individuals with type 1 diabetes and has potential long-term adverse consequences.”
Dr. Braffett outlined the new study approaches added in 2022-2027. Cardiopulmonary exercise testing, two-dimensional Doppler echocardiography, and carotid-femoral pulse wave velocity will be used to quantify functional and structural changes central to heart failure.
Dr. Nathan commented that, although enough cardiovascular events were available in EDIC by 2006 to demonstrate a significant 58% reduction in the intensive therapy group, “now we can start looking at the aging heart. We have a bunch of great cardiologists working with us who will be guiding us on measuring everything.”
Fatty liver disease in the setting of increasing adiposity will also be investigated using transient elastography (FibroScan) and the Fibrosis-4 index, a quantification of liver enzymes and platelet count.
Dr. Nathan noted that the study participants have had “this kind of funny metabolic milieu in their liver for decades. They don’t make insulin in their pancreas, and therefore, the insulin they get is peripheral and then it goes to their liver. Well, what does that do to them?”
Participants will also complete three symptom questionnaires assessing obstructive sleep apnea, aimed at guiding future sleep studies in those found to be at high risk, Dr. Braffett said.
DCCT/EDIC over 40 years: ‘Incredibly complete picture’
As of 2023, the DCCT/EDIC participants have been studied for longer than 60% of their lifespans and for over 80% of their diabetes duration, Dr. Braffett noted.
During the EDIC 2017-2022 cycle, Dr. Braffett and other speakers summarized, prior EDIC efforts had focused on aspects of cognitive function, physical function, and cheiroarthropathy.
Other DCCT/EDIC studies examined the relationship of A1c and diabetes duration in cardiovascular disease risk, the association of microvascular complications with the risk of cardiovascular disease beyond traditional risk factors, and the risk of severe hypoglycemia over the first 30 years of DCCT/EDIC follow-up.
Moreover, the longitudinal eye and kidney assessments over the 40 years have informed screening guidelines for retinopathy and urinary albumin.
Dr. Nathan said: “Today, the number with horrible complications is very few, but we haven’t erased complications entirely. ... We have this incredibly complete picture of type 1 diabetes that allows us to explore everything. We welcome people to come to us with ideas. That’s the value of this research.”
Dr. Nathan, Ms. Lorenzi, and Dr. Braffett reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
SAN DIEGO –
New funding for 2022-2027 for the DCCT long-term observational follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC) will go toward investigating aspects of type 1 diabetes that are associated with aging and are also common in type 2 diabetes, including cardiovascular disease, fatty liver disease, and sleep apnea.
The original randomized DCCT clinical trial results, published in 1993 in the New England Journal of Medicine, proved that early intensive glycemic control was the key to preventing or slowing the progression of long-term eye, kidney, and nerve complications of type 1 diabetes. Subsequently, EDIC has yielded many more major findings including that early tight glycemic control also reduces cardiovascular risk and prolongs survival in type 1 diabetes.
And although the phenomenon of metabolic memory initially seen in EDIC means that early glycemic control is important, subsequent EDIC data also have suggested that it is never too late to initiate intensive glycemic control, speakers emphasized during a special symposium commemorating 40 years since the start of DCCT, held during the annual scientific sessions of the American Diabetes Association. As with the 30-year DCCT/EDIC commemorative symposium held in 2013, local study participants were in the audience and were acknowledged with long applause.
Together, DCCT and EDIC – both funded by the National Institutes of Health at 27 sites in the United States and Canada – have changed the standard of care for people with type 1 diabetes and continue to inform clinical practice. Prior to the DCCT, between 1930 and 1970, about a third of people with type 1 diabetes developed vision loss and one in five experienced kidney failure and/or myocardial infarction. Stroke and amputation were also common, DCCT/EDIC chair David M. Nathan, MD, said while introducing the symposium.
“All of the advances in care of type 1 diabetes have developed because this study demonstrated that it was important – continuous glucose monitoring (CGM), new insulins, better [insulin] pumps. ... I think the most profound finding is that mortality in our intensively treated cohort is the same as in the general population. That says it all,” Dr. Nathan said in an interview.
And now, “what we still have yet to contribute is what happens to type 1 diabetes as people get older,” added Dr. Nathan, a professor of medicine at Harvard Medical School and director of the Diabetes Center at Massachusetts General Hospital, both in Boston.
‘Something that heretofore none of us could have imagined’
The 1,441 DCCT participants had a mean age of 27 years at baseline in 1983, when they were randomized to intensive insulin therapy or usual care. The 1,375 participants (96%) who continued into EDIC in 1994 were an average of 35 years old at that point, when the usual care group was taught intensive glycemic management and all participants returned to their personal health care teams. The 1,075 participants in EDIC today are an average age of 63 years.
Only 11 participants had died at the start of EDIC, and just 250 (17%) have died as of 2023, said study coordinator cochair Gayle Lorenzi, RN, who is a certified diabetes care and education specialist at the University of California, San Diego.
“DCCT/EDIC because of its longevity represents a unique opportunity to explore aging in long duration of type 1 diabetes, something that heretofore none of us could have imagined, especially for those of you in the audience who started your careers in the 70s and 80s,” Ms. Lorenzi commented.
About 36% of the cohort now has overweight and 40% have obesity, mirroring the general population. And they now have a mean hemoglobin A1c of 7.3%.
According to Barbara H. Braffett, PhD, co–principal investigator at the DCCT/EDIC data coordinating center: “The EDIC study is now shifting its focus during the next 5 years to understand the clinical course of type 1 diabetes in the setting of advancing duration and age, as well as increasing adiposity, which has progressively affected individuals with type 1 diabetes and has potential long-term adverse consequences.”
Dr. Braffett outlined the new study approaches added in 2022-2027. Cardiopulmonary exercise testing, two-dimensional Doppler echocardiography, and carotid-femoral pulse wave velocity will be used to quantify functional and structural changes central to heart failure.
Dr. Nathan commented that, although enough cardiovascular events were available in EDIC by 2006 to demonstrate a significant 58% reduction in the intensive therapy group, “now we can start looking at the aging heart. We have a bunch of great cardiologists working with us who will be guiding us on measuring everything.”
Fatty liver disease in the setting of increasing adiposity will also be investigated using transient elastography (FibroScan) and the Fibrosis-4 index, a quantification of liver enzymes and platelet count.
Dr. Nathan noted that the study participants have had “this kind of funny metabolic milieu in their liver for decades. They don’t make insulin in their pancreas, and therefore, the insulin they get is peripheral and then it goes to their liver. Well, what does that do to them?”
Participants will also complete three symptom questionnaires assessing obstructive sleep apnea, aimed at guiding future sleep studies in those found to be at high risk, Dr. Braffett said.
DCCT/EDIC over 40 years: ‘Incredibly complete picture’
As of 2023, the DCCT/EDIC participants have been studied for longer than 60% of their lifespans and for over 80% of their diabetes duration, Dr. Braffett noted.
During the EDIC 2017-2022 cycle, Dr. Braffett and other speakers summarized, prior EDIC efforts had focused on aspects of cognitive function, physical function, and cheiroarthropathy.
Other DCCT/EDIC studies examined the relationship of A1c and diabetes duration in cardiovascular disease risk, the association of microvascular complications with the risk of cardiovascular disease beyond traditional risk factors, and the risk of severe hypoglycemia over the first 30 years of DCCT/EDIC follow-up.
Moreover, the longitudinal eye and kidney assessments over the 40 years have informed screening guidelines for retinopathy and urinary albumin.
Dr. Nathan said: “Today, the number with horrible complications is very few, but we haven’t erased complications entirely. ... We have this incredibly complete picture of type 1 diabetes that allows us to explore everything. We welcome people to come to us with ideas. That’s the value of this research.”
Dr. Nathan, Ms. Lorenzi, and Dr. Braffett reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
SAN DIEGO –
New funding for 2022-2027 for the DCCT long-term observational follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC) will go toward investigating aspects of type 1 diabetes that are associated with aging and are also common in type 2 diabetes, including cardiovascular disease, fatty liver disease, and sleep apnea.
The original randomized DCCT clinical trial results, published in 1993 in the New England Journal of Medicine, proved that early intensive glycemic control was the key to preventing or slowing the progression of long-term eye, kidney, and nerve complications of type 1 diabetes. Subsequently, EDIC has yielded many more major findings including that early tight glycemic control also reduces cardiovascular risk and prolongs survival in type 1 diabetes.
And although the phenomenon of metabolic memory initially seen in EDIC means that early glycemic control is important, subsequent EDIC data also have suggested that it is never too late to initiate intensive glycemic control, speakers emphasized during a special symposium commemorating 40 years since the start of DCCT, held during the annual scientific sessions of the American Diabetes Association. As with the 30-year DCCT/EDIC commemorative symposium held in 2013, local study participants were in the audience and were acknowledged with long applause.
Together, DCCT and EDIC – both funded by the National Institutes of Health at 27 sites in the United States and Canada – have changed the standard of care for people with type 1 diabetes and continue to inform clinical practice. Prior to the DCCT, between 1930 and 1970, about a third of people with type 1 diabetes developed vision loss and one in five experienced kidney failure and/or myocardial infarction. Stroke and amputation were also common, DCCT/EDIC chair David M. Nathan, MD, said while introducing the symposium.
“All of the advances in care of type 1 diabetes have developed because this study demonstrated that it was important – continuous glucose monitoring (CGM), new insulins, better [insulin] pumps. ... I think the most profound finding is that mortality in our intensively treated cohort is the same as in the general population. That says it all,” Dr. Nathan said in an interview.
And now, “what we still have yet to contribute is what happens to type 1 diabetes as people get older,” added Dr. Nathan, a professor of medicine at Harvard Medical School and director of the Diabetes Center at Massachusetts General Hospital, both in Boston.
‘Something that heretofore none of us could have imagined’
The 1,441 DCCT participants had a mean age of 27 years at baseline in 1983, when they were randomized to intensive insulin therapy or usual care. The 1,375 participants (96%) who continued into EDIC in 1994 were an average of 35 years old at that point, when the usual care group was taught intensive glycemic management and all participants returned to their personal health care teams. The 1,075 participants in EDIC today are an average age of 63 years.
Only 11 participants had died at the start of EDIC, and just 250 (17%) have died as of 2023, said study coordinator cochair Gayle Lorenzi, RN, who is a certified diabetes care and education specialist at the University of California, San Diego.
“DCCT/EDIC because of its longevity represents a unique opportunity to explore aging in long duration of type 1 diabetes, something that heretofore none of us could have imagined, especially for those of you in the audience who started your careers in the 70s and 80s,” Ms. Lorenzi commented.
About 36% of the cohort now has overweight and 40% have obesity, mirroring the general population. And they now have a mean hemoglobin A1c of 7.3%.
According to Barbara H. Braffett, PhD, co–principal investigator at the DCCT/EDIC data coordinating center: “The EDIC study is now shifting its focus during the next 5 years to understand the clinical course of type 1 diabetes in the setting of advancing duration and age, as well as increasing adiposity, which has progressively affected individuals with type 1 diabetes and has potential long-term adverse consequences.”
Dr. Braffett outlined the new study approaches added in 2022-2027. Cardiopulmonary exercise testing, two-dimensional Doppler echocardiography, and carotid-femoral pulse wave velocity will be used to quantify functional and structural changes central to heart failure.
Dr. Nathan commented that, although enough cardiovascular events were available in EDIC by 2006 to demonstrate a significant 58% reduction in the intensive therapy group, “now we can start looking at the aging heart. We have a bunch of great cardiologists working with us who will be guiding us on measuring everything.”
Fatty liver disease in the setting of increasing adiposity will also be investigated using transient elastography (FibroScan) and the Fibrosis-4 index, a quantification of liver enzymes and platelet count.
Dr. Nathan noted that the study participants have had “this kind of funny metabolic milieu in their liver for decades. They don’t make insulin in their pancreas, and therefore, the insulin they get is peripheral and then it goes to their liver. Well, what does that do to them?”
Participants will also complete three symptom questionnaires assessing obstructive sleep apnea, aimed at guiding future sleep studies in those found to be at high risk, Dr. Braffett said.
DCCT/EDIC over 40 years: ‘Incredibly complete picture’
As of 2023, the DCCT/EDIC participants have been studied for longer than 60% of their lifespans and for over 80% of their diabetes duration, Dr. Braffett noted.
During the EDIC 2017-2022 cycle, Dr. Braffett and other speakers summarized, prior EDIC efforts had focused on aspects of cognitive function, physical function, and cheiroarthropathy.
Other DCCT/EDIC studies examined the relationship of A1c and diabetes duration in cardiovascular disease risk, the association of microvascular complications with the risk of cardiovascular disease beyond traditional risk factors, and the risk of severe hypoglycemia over the first 30 years of DCCT/EDIC follow-up.
Moreover, the longitudinal eye and kidney assessments over the 40 years have informed screening guidelines for retinopathy and urinary albumin.
Dr. Nathan said: “Today, the number with horrible complications is very few, but we haven’t erased complications entirely. ... We have this incredibly complete picture of type 1 diabetes that allows us to explore everything. We welcome people to come to us with ideas. That’s the value of this research.”
Dr. Nathan, Ms. Lorenzi, and Dr. Braffett reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ADA 2023
COORDINATE-Diabetes: A ‘wake-up call’ for many specialties
SAN DIEGO – at the annual scientific sessions of the American Diabetes Association.
A symposium there focused on the recent randomized, controlled COORDINATE-Diabetes trial, which investigated a multipronged educational intervention in 43 U.S. cardiology clinics aimed at improving prescribing of guideline-recommended treatments for people with both type 2 diabetes and cardiovascular disease. Compared with clinics that were randomly assigned to offer usual care, the intervention significantly increased recommended prescribing of high-intensity statins, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ARBs), and sodium-glucose cotransporter 2 (SGLT2) inhibitors and/or glucagonlike peptide 1 receptor agonists (GLP-1 agonists).
COORDINATE-Diabetes was aimed at cardiologists, who typically see these patients more often than do endocrinologists. However, the results are relevant to all health care providers involved in the care of those with type 2 diabetes, speakers argued at the ADA symposium.
“This is a cardiology study. I think it’s safe to say that not too many of you in the room are cardiologists. So why would you care about the results of the COORDINATE study?” said Ildiko Lingvay, MD, of the University of Texas Southwestern Medical Center, Dallas.
Dr. Lingvay went on to outline reasons that the COORDINATE findings apply to endocrinologists and primary care clinicians, as well as cardiologists. For one, a study from her institution that was presented at a recent internal medicine meeting showed that, among more than 10,000 patients with type 2 diabetes and cardiovascular disease, heart failure, and/or chronic kidney disease, the proportion of patients who were prescribed the appropriate guideline-indicated medications was 20.1% for those seen in primary care, 24.8% in endocrinology, 20.3% in cardiology, and 18.3% in nephrology.
“So, we [endocrinologists are] not that much better [than other specialties]” at prescribing, she noted.
Mikhail N. Kosiborod, MD, in independent commentary called the COORDINATE trial and other similar initiatives “the beginning of care transformation.”
The COORDINATE-Diabetes results were originally presented in March at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The study was simultaneously published in JAMA.
‘They’ve shown we can do better’
Asked to comment, Robert H. Eckel, MD, said in an interview, “I look at COORDINATE as a wake-up call to the need for multispecialty approaches to people with type 2 diabetes and cardiovascular disease. ... I think it’s a step in the door.”
Dr. Eckel, who has long advocated for a new “cardiometabolic” physician subspecialty, noted that COORDINATE-Diabetes “stopped short of training health care providers in the science and medicine of cardio-renal-metabolic disease.”
Nonetheless, regarding the efforts toward a more coordinated system of care, Dr. Eckel said, “I support the concept, unequivocally.” He is associated with the division of endocrinology, metabolism, and diabetes, University of Colorado at Denver, Aurora.
But the cost-effectiveness of the intervention “requires time to assess,” he added. “We don’t know anything yet other than [that] managing drug administration to meet goals that relate to outcomes in people with diabetes can be accomplished. They’ve shown that we can do better.”
Why should you care about a cardiology study?
In COORDINATE-Diabetes, 20 of the centers were randomly assigned to provide five interventions: assess local barriers, develop care pathways, coordinate care, educate clinicians, report data back to the clinics, and provide tools for the 459 participants. The other 23 clinics, with 590 participants, were randomly assigned to provide usual care per practice guidelines.
The primary outcome was the proportion of participants that prescribed all three groups of the recommended therapies at 6-12 months after enrollment; 37.9% prescribed the intervention, and 14.5% provided usual care, a significant 23% difference (P < .001). The rate of prescriptions of each of the three individual drug groups was also significantly higher with the intervention. No differences were seen in cardiovascular risk factors or outcomes.
Dr. Lingvay pointed out that the interventions tested in COORDINATE – such as fact sheets and medication passports for patients, system audits and feedback, and provider grand rounds – can be extrapolated to any specialist setting.
She added that the long-held model of team-based care means that “everyone involved in the care of these patients is responsible for ensuring best practices are followed.” Part of that, she said, is helping other specialists prescribe the same medications and communicate across the team.
For all specialists, she recommends using the resources available on the COORDINATE website.
‘It’s not a silver bullet; additional solutions are needed’
In his commentary, Dr. Kosiborod, executive director of the Cardiometabolic Center Alliance, noted, “The treatments studied in COORDINATE represent the biggest advances in a generation when it comes to improving outcomes in this population. ... We’re living in a renaissance age with the number of tools we have available. ... It’s getting better every day.”
Moreover, all the relevant professional society guidelines now recommend GLP-1 agonists and SGLT2 inhibitors. “And yet, when we look, less than 1 in 10 patients with type 2 diabetes and atherosclerotic cardiovascular disease are getting appropriate recommended care. One of the lessons of COORDINATE is that this needs to change if we’re really going to improve our patients’ lives.”
The barriers aren’t simply financial, Dr. Kosiborod said. He pointed to two studies that show that even reducing out-of-pocket costs resulted in only modest increases in adherence.
Educational gaps on the part of both clinicians and patients also factor in, as do misaligned incentives.
“Clinicians get paid for how many things they do, not necessarily how well they do them. Everyone wants to do the right thing, but ultimately, incentives do matter,” he emphasized.
While the COORDINATE-Diabetes interventions addressed several of the barriers, two-thirds of the participants still did not receive optimal therapy.
“It’s not a silver bullet. ... Additional solutions are needed,” Dr. Kosiborod observed.
Transformation occurs ‘when the status quo is no longer acceptable’
Enter his institution, the Cardiometabolic Center Alliance, part of Saint Luke’s Mid-America Heart Institute. The nonprofit system, which currently has 16 subscribing clinics around the country, offers patient-centered “team-based, coordinated, comprehensive care” for people with both type 2 diabetes and cardiovascular disease.
The model is led by preventive cardiology in collaboration with endocrinology and primary care. Support staff includes advance practice providers, nurse navigators, certified diabetes educators, dietitians, and pharmacists. Individualized treatment plans aim for “aggressive secondary risk reduction,” Dr. Kosiborod noted.
Six-month data from the Cardiometabolic Center Alliance show an increase from 28.2% at baseline to 67.1% (P < .0001) in prescribing of a four-agent guideline-directed medical therapy “bundle,” including the three from COORDINATE-Diabetes plus an antiplatelet or anticoagulant agent. Dr. Kosiborod presented these data during the ADA meeting in a poster.
Remaining questions involve sustainability, scalability, and system transformation, which require buy-in from multiple stakeholders, he noted.
He contends that it can be done. A prior example of “rapid and lasting care transformation” occurred in November 2006 with the launch of the “Door to Balloon (D2B) Alliance for Quality,” which dramatically increased the proportion of patients who received primary angioplasty within 90 minutes at hospitals around the United States. From January 2005 to September 2010, those proportions rose from 27.3% to 70.4%.
“Patients were coming into the emergency department with myocardial infarctions and waiting for hours before the interventional cardiologist came. The community said we needed a nationwide quality improvement initiative. ... Almost every hospital in the country changed their systems of care. It was a huge national effort. ... When we no longer consider the status quo acceptable, we can actually make something very special happen very quickly.”
After the session, Dr. Kosiborod said in an interview that the Cardiometabolic Center Alliance is now gathering data to make the financial case for the approach.
“We’re trying to develop a model that tells the admins which patients will save money, because, of course, if you can create a financial incentive, it only makes it go faster. ... We want to synchronize it in the best way possible.”
Dr. Lingvay has receiving nonfinancial support and grants from Novo Nordisk, personal fees or nonfinancial support from Sanofi, Lilly, Boehringer Ingelheim, Merck/Pfizer, Mylan, AstraZeneca, Johnson & Johnson, Intercept, Target Pharma, Zealand, Shionogi, Carmot, Structure, Bayer, Mediflix, WebMD, GI Dynamics, Intarcia Therapeutics, Mannkind, Novartis, Structure Therapeutics, and Valeritas. Dr. Kosiborod is a consultant for Alnylam Pharmaceuticals, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, ESPERION Therapeutics, Janssen Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, Vifor Pharma Management, and Youngene Therapeutics. He also receives research support from AstraZeneca and Boehringer Ingelheim. Dr. Eckel serves on consulting/advisory boards for Amgen, Arrowhead, Better, Ionis, Kowa, Lexicon, Novo Nordisk, Precision BioSciences, The Healthy Aging Company, Tolmar, and Weight Watchers.
A version of this article first appeared on Medscape.com.
SAN DIEGO – at the annual scientific sessions of the American Diabetes Association.
A symposium there focused on the recent randomized, controlled COORDINATE-Diabetes trial, which investigated a multipronged educational intervention in 43 U.S. cardiology clinics aimed at improving prescribing of guideline-recommended treatments for people with both type 2 diabetes and cardiovascular disease. Compared with clinics that were randomly assigned to offer usual care, the intervention significantly increased recommended prescribing of high-intensity statins, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ARBs), and sodium-glucose cotransporter 2 (SGLT2) inhibitors and/or glucagonlike peptide 1 receptor agonists (GLP-1 agonists).
COORDINATE-Diabetes was aimed at cardiologists, who typically see these patients more often than do endocrinologists. However, the results are relevant to all health care providers involved in the care of those with type 2 diabetes, speakers argued at the ADA symposium.
“This is a cardiology study. I think it’s safe to say that not too many of you in the room are cardiologists. So why would you care about the results of the COORDINATE study?” said Ildiko Lingvay, MD, of the University of Texas Southwestern Medical Center, Dallas.
Dr. Lingvay went on to outline reasons that the COORDINATE findings apply to endocrinologists and primary care clinicians, as well as cardiologists. For one, a study from her institution that was presented at a recent internal medicine meeting showed that, among more than 10,000 patients with type 2 diabetes and cardiovascular disease, heart failure, and/or chronic kidney disease, the proportion of patients who were prescribed the appropriate guideline-indicated medications was 20.1% for those seen in primary care, 24.8% in endocrinology, 20.3% in cardiology, and 18.3% in nephrology.
“So, we [endocrinologists are] not that much better [than other specialties]” at prescribing, she noted.
Mikhail N. Kosiborod, MD, in independent commentary called the COORDINATE trial and other similar initiatives “the beginning of care transformation.”
The COORDINATE-Diabetes results were originally presented in March at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The study was simultaneously published in JAMA.
‘They’ve shown we can do better’
Asked to comment, Robert H. Eckel, MD, said in an interview, “I look at COORDINATE as a wake-up call to the need for multispecialty approaches to people with type 2 diabetes and cardiovascular disease. ... I think it’s a step in the door.”
Dr. Eckel, who has long advocated for a new “cardiometabolic” physician subspecialty, noted that COORDINATE-Diabetes “stopped short of training health care providers in the science and medicine of cardio-renal-metabolic disease.”
Nonetheless, regarding the efforts toward a more coordinated system of care, Dr. Eckel said, “I support the concept, unequivocally.” He is associated with the division of endocrinology, metabolism, and diabetes, University of Colorado at Denver, Aurora.
But the cost-effectiveness of the intervention “requires time to assess,” he added. “We don’t know anything yet other than [that] managing drug administration to meet goals that relate to outcomes in people with diabetes can be accomplished. They’ve shown that we can do better.”
Why should you care about a cardiology study?
In COORDINATE-Diabetes, 20 of the centers were randomly assigned to provide five interventions: assess local barriers, develop care pathways, coordinate care, educate clinicians, report data back to the clinics, and provide tools for the 459 participants. The other 23 clinics, with 590 participants, were randomly assigned to provide usual care per practice guidelines.
The primary outcome was the proportion of participants that prescribed all three groups of the recommended therapies at 6-12 months after enrollment; 37.9% prescribed the intervention, and 14.5% provided usual care, a significant 23% difference (P < .001). The rate of prescriptions of each of the three individual drug groups was also significantly higher with the intervention. No differences were seen in cardiovascular risk factors or outcomes.
Dr. Lingvay pointed out that the interventions tested in COORDINATE – such as fact sheets and medication passports for patients, system audits and feedback, and provider grand rounds – can be extrapolated to any specialist setting.
She added that the long-held model of team-based care means that “everyone involved in the care of these patients is responsible for ensuring best practices are followed.” Part of that, she said, is helping other specialists prescribe the same medications and communicate across the team.
For all specialists, she recommends using the resources available on the COORDINATE website.
‘It’s not a silver bullet; additional solutions are needed’
In his commentary, Dr. Kosiborod, executive director of the Cardiometabolic Center Alliance, noted, “The treatments studied in COORDINATE represent the biggest advances in a generation when it comes to improving outcomes in this population. ... We’re living in a renaissance age with the number of tools we have available. ... It’s getting better every day.”
Moreover, all the relevant professional society guidelines now recommend GLP-1 agonists and SGLT2 inhibitors. “And yet, when we look, less than 1 in 10 patients with type 2 diabetes and atherosclerotic cardiovascular disease are getting appropriate recommended care. One of the lessons of COORDINATE is that this needs to change if we’re really going to improve our patients’ lives.”
The barriers aren’t simply financial, Dr. Kosiborod said. He pointed to two studies that show that even reducing out-of-pocket costs resulted in only modest increases in adherence.
Educational gaps on the part of both clinicians and patients also factor in, as do misaligned incentives.
“Clinicians get paid for how many things they do, not necessarily how well they do them. Everyone wants to do the right thing, but ultimately, incentives do matter,” he emphasized.
While the COORDINATE-Diabetes interventions addressed several of the barriers, two-thirds of the participants still did not receive optimal therapy.
“It’s not a silver bullet. ... Additional solutions are needed,” Dr. Kosiborod observed.
Transformation occurs ‘when the status quo is no longer acceptable’
Enter his institution, the Cardiometabolic Center Alliance, part of Saint Luke’s Mid-America Heart Institute. The nonprofit system, which currently has 16 subscribing clinics around the country, offers patient-centered “team-based, coordinated, comprehensive care” for people with both type 2 diabetes and cardiovascular disease.
The model is led by preventive cardiology in collaboration with endocrinology and primary care. Support staff includes advance practice providers, nurse navigators, certified diabetes educators, dietitians, and pharmacists. Individualized treatment plans aim for “aggressive secondary risk reduction,” Dr. Kosiborod noted.
Six-month data from the Cardiometabolic Center Alliance show an increase from 28.2% at baseline to 67.1% (P < .0001) in prescribing of a four-agent guideline-directed medical therapy “bundle,” including the three from COORDINATE-Diabetes plus an antiplatelet or anticoagulant agent. Dr. Kosiborod presented these data during the ADA meeting in a poster.
Remaining questions involve sustainability, scalability, and system transformation, which require buy-in from multiple stakeholders, he noted.
He contends that it can be done. A prior example of “rapid and lasting care transformation” occurred in November 2006 with the launch of the “Door to Balloon (D2B) Alliance for Quality,” which dramatically increased the proportion of patients who received primary angioplasty within 90 minutes at hospitals around the United States. From January 2005 to September 2010, those proportions rose from 27.3% to 70.4%.
“Patients were coming into the emergency department with myocardial infarctions and waiting for hours before the interventional cardiologist came. The community said we needed a nationwide quality improvement initiative. ... Almost every hospital in the country changed their systems of care. It was a huge national effort. ... When we no longer consider the status quo acceptable, we can actually make something very special happen very quickly.”
After the session, Dr. Kosiborod said in an interview that the Cardiometabolic Center Alliance is now gathering data to make the financial case for the approach.
“We’re trying to develop a model that tells the admins which patients will save money, because, of course, if you can create a financial incentive, it only makes it go faster. ... We want to synchronize it in the best way possible.”
Dr. Lingvay has receiving nonfinancial support and grants from Novo Nordisk, personal fees or nonfinancial support from Sanofi, Lilly, Boehringer Ingelheim, Merck/Pfizer, Mylan, AstraZeneca, Johnson & Johnson, Intercept, Target Pharma, Zealand, Shionogi, Carmot, Structure, Bayer, Mediflix, WebMD, GI Dynamics, Intarcia Therapeutics, Mannkind, Novartis, Structure Therapeutics, and Valeritas. Dr. Kosiborod is a consultant for Alnylam Pharmaceuticals, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, ESPERION Therapeutics, Janssen Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, Vifor Pharma Management, and Youngene Therapeutics. He also receives research support from AstraZeneca and Boehringer Ingelheim. Dr. Eckel serves on consulting/advisory boards for Amgen, Arrowhead, Better, Ionis, Kowa, Lexicon, Novo Nordisk, Precision BioSciences, The Healthy Aging Company, Tolmar, and Weight Watchers.
A version of this article first appeared on Medscape.com.
SAN DIEGO – at the annual scientific sessions of the American Diabetes Association.
A symposium there focused on the recent randomized, controlled COORDINATE-Diabetes trial, which investigated a multipronged educational intervention in 43 U.S. cardiology clinics aimed at improving prescribing of guideline-recommended treatments for people with both type 2 diabetes and cardiovascular disease. Compared with clinics that were randomly assigned to offer usual care, the intervention significantly increased recommended prescribing of high-intensity statins, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ARBs), and sodium-glucose cotransporter 2 (SGLT2) inhibitors and/or glucagonlike peptide 1 receptor agonists (GLP-1 agonists).
COORDINATE-Diabetes was aimed at cardiologists, who typically see these patients more often than do endocrinologists. However, the results are relevant to all health care providers involved in the care of those with type 2 diabetes, speakers argued at the ADA symposium.
“This is a cardiology study. I think it’s safe to say that not too many of you in the room are cardiologists. So why would you care about the results of the COORDINATE study?” said Ildiko Lingvay, MD, of the University of Texas Southwestern Medical Center, Dallas.
Dr. Lingvay went on to outline reasons that the COORDINATE findings apply to endocrinologists and primary care clinicians, as well as cardiologists. For one, a study from her institution that was presented at a recent internal medicine meeting showed that, among more than 10,000 patients with type 2 diabetes and cardiovascular disease, heart failure, and/or chronic kidney disease, the proportion of patients who were prescribed the appropriate guideline-indicated medications was 20.1% for those seen in primary care, 24.8% in endocrinology, 20.3% in cardiology, and 18.3% in nephrology.
“So, we [endocrinologists are] not that much better [than other specialties]” at prescribing, she noted.
Mikhail N. Kosiborod, MD, in independent commentary called the COORDINATE trial and other similar initiatives “the beginning of care transformation.”
The COORDINATE-Diabetes results were originally presented in March at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The study was simultaneously published in JAMA.
‘They’ve shown we can do better’
Asked to comment, Robert H. Eckel, MD, said in an interview, “I look at COORDINATE as a wake-up call to the need for multispecialty approaches to people with type 2 diabetes and cardiovascular disease. ... I think it’s a step in the door.”
Dr. Eckel, who has long advocated for a new “cardiometabolic” physician subspecialty, noted that COORDINATE-Diabetes “stopped short of training health care providers in the science and medicine of cardio-renal-metabolic disease.”
Nonetheless, regarding the efforts toward a more coordinated system of care, Dr. Eckel said, “I support the concept, unequivocally.” He is associated with the division of endocrinology, metabolism, and diabetes, University of Colorado at Denver, Aurora.
But the cost-effectiveness of the intervention “requires time to assess,” he added. “We don’t know anything yet other than [that] managing drug administration to meet goals that relate to outcomes in people with diabetes can be accomplished. They’ve shown that we can do better.”
Why should you care about a cardiology study?
In COORDINATE-Diabetes, 20 of the centers were randomly assigned to provide five interventions: assess local barriers, develop care pathways, coordinate care, educate clinicians, report data back to the clinics, and provide tools for the 459 participants. The other 23 clinics, with 590 participants, were randomly assigned to provide usual care per practice guidelines.
The primary outcome was the proportion of participants that prescribed all three groups of the recommended therapies at 6-12 months after enrollment; 37.9% prescribed the intervention, and 14.5% provided usual care, a significant 23% difference (P < .001). The rate of prescriptions of each of the three individual drug groups was also significantly higher with the intervention. No differences were seen in cardiovascular risk factors or outcomes.
Dr. Lingvay pointed out that the interventions tested in COORDINATE – such as fact sheets and medication passports for patients, system audits and feedback, and provider grand rounds – can be extrapolated to any specialist setting.
She added that the long-held model of team-based care means that “everyone involved in the care of these patients is responsible for ensuring best practices are followed.” Part of that, she said, is helping other specialists prescribe the same medications and communicate across the team.
For all specialists, she recommends using the resources available on the COORDINATE website.
‘It’s not a silver bullet; additional solutions are needed’
In his commentary, Dr. Kosiborod, executive director of the Cardiometabolic Center Alliance, noted, “The treatments studied in COORDINATE represent the biggest advances in a generation when it comes to improving outcomes in this population. ... We’re living in a renaissance age with the number of tools we have available. ... It’s getting better every day.”
Moreover, all the relevant professional society guidelines now recommend GLP-1 agonists and SGLT2 inhibitors. “And yet, when we look, less than 1 in 10 patients with type 2 diabetes and atherosclerotic cardiovascular disease are getting appropriate recommended care. One of the lessons of COORDINATE is that this needs to change if we’re really going to improve our patients’ lives.”
The barriers aren’t simply financial, Dr. Kosiborod said. He pointed to two studies that show that even reducing out-of-pocket costs resulted in only modest increases in adherence.
Educational gaps on the part of both clinicians and patients also factor in, as do misaligned incentives.
“Clinicians get paid for how many things they do, not necessarily how well they do them. Everyone wants to do the right thing, but ultimately, incentives do matter,” he emphasized.
While the COORDINATE-Diabetes interventions addressed several of the barriers, two-thirds of the participants still did not receive optimal therapy.
“It’s not a silver bullet. ... Additional solutions are needed,” Dr. Kosiborod observed.
Transformation occurs ‘when the status quo is no longer acceptable’
Enter his institution, the Cardiometabolic Center Alliance, part of Saint Luke’s Mid-America Heart Institute. The nonprofit system, which currently has 16 subscribing clinics around the country, offers patient-centered “team-based, coordinated, comprehensive care” for people with both type 2 diabetes and cardiovascular disease.
The model is led by preventive cardiology in collaboration with endocrinology and primary care. Support staff includes advance practice providers, nurse navigators, certified diabetes educators, dietitians, and pharmacists. Individualized treatment plans aim for “aggressive secondary risk reduction,” Dr. Kosiborod noted.
Six-month data from the Cardiometabolic Center Alliance show an increase from 28.2% at baseline to 67.1% (P < .0001) in prescribing of a four-agent guideline-directed medical therapy “bundle,” including the three from COORDINATE-Diabetes plus an antiplatelet or anticoagulant agent. Dr. Kosiborod presented these data during the ADA meeting in a poster.
Remaining questions involve sustainability, scalability, and system transformation, which require buy-in from multiple stakeholders, he noted.
He contends that it can be done. A prior example of “rapid and lasting care transformation” occurred in November 2006 with the launch of the “Door to Balloon (D2B) Alliance for Quality,” which dramatically increased the proportion of patients who received primary angioplasty within 90 minutes at hospitals around the United States. From January 2005 to September 2010, those proportions rose from 27.3% to 70.4%.
“Patients were coming into the emergency department with myocardial infarctions and waiting for hours before the interventional cardiologist came. The community said we needed a nationwide quality improvement initiative. ... Almost every hospital in the country changed their systems of care. It was a huge national effort. ... When we no longer consider the status quo acceptable, we can actually make something very special happen very quickly.”
After the session, Dr. Kosiborod said in an interview that the Cardiometabolic Center Alliance is now gathering data to make the financial case for the approach.
“We’re trying to develop a model that tells the admins which patients will save money, because, of course, if you can create a financial incentive, it only makes it go faster. ... We want to synchronize it in the best way possible.”
Dr. Lingvay has receiving nonfinancial support and grants from Novo Nordisk, personal fees or nonfinancial support from Sanofi, Lilly, Boehringer Ingelheim, Merck/Pfizer, Mylan, AstraZeneca, Johnson & Johnson, Intercept, Target Pharma, Zealand, Shionogi, Carmot, Structure, Bayer, Mediflix, WebMD, GI Dynamics, Intarcia Therapeutics, Mannkind, Novartis, Structure Therapeutics, and Valeritas. Dr. Kosiborod is a consultant for Alnylam Pharmaceuticals, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, ESPERION Therapeutics, Janssen Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, Vifor Pharma Management, and Youngene Therapeutics. He also receives research support from AstraZeneca and Boehringer Ingelheim. Dr. Eckel serves on consulting/advisory boards for Amgen, Arrowhead, Better, Ionis, Kowa, Lexicon, Novo Nordisk, Precision BioSciences, The Healthy Aging Company, Tolmar, and Weight Watchers.
A version of this article first appeared on Medscape.com.
AT ADA 2023
Thirty-three percent of type 1 diabetes patients insulin free with stem cells
SAN DIEGO – An investigational allogeneic stem cell–derived pancreatic islet cell replacement therapy (VX-880, Vertex Pharmaceuticals) continues to show promise as a treatment for type 1 diabetes, according to the latest data, from six patients thus far.
Two of the six are insulin-independent beyond 1 year after receiving the VX-880 infusions, and three others who received them more recently are on a similar trajectory. One dropped out because of reasons unrelated to the therapy. The remaining five are continuing to receive immunosuppressive treatment to prevent rejection of the islets. The six all had undetectable insulin secretion, impaired hypoglycemic awareness, and severe hypoglycemia as the criterion to enter the phase 1/2 study.
“These new findings demonstrate the potential of stem cell–derived islets as a future treatment for patients with type 1 diabetes, signaling a new era that could potentially remove the need for exogenously administered insulin to achieve glycemic control,” said lead investigator Trevor W. Reichman, MD, PhD, surgical director of Pancreas and Islet Cell Transplantation at the University of Toronto.
Dr. Reichman presented the data at the annual scientific sessions of the American Diabetes Association, as an update to the report of the first two patients at last year’s ADA meeting. “We are hopeful that this first-of-its-kind research could be a game-changer for the treatment of type 1 diabetes,” he emphasized.
Co-investigator Maria Cristina Nostro, PhD, senior scientist at McEwen Stem Cell Institute, Toronto, told this news organization: “The clinical trial data are extremely exciting ... I think what was very beautiful is the glucose tolerance test where the insulin secretion was almost like a person without type 1 diabetes. For someone who is in the lab doing basic science research ... all the work we’ve put into this, it’s a labor of love. We’ve been trying to generate the cells for so long, and now to see this, it’s fantastic.”
Two meet primary endpoint, three more on the right path
The six patients had a mean age of 44 years and mean 23 years’ diabetes duration. Three each were male and female. Their mean baseline A1c was 8.1%, and fasting C-peptide was undetectable. They had experienced a mean of 3.3 severe hypoglycemia episodes in the year prior to receiving the infusion, which was delivered to the portal vein similarly to the procedure with cadaveric donor islets, Dr. Reichman said.
The first two patients, including the one who dropped out, received half target doses of VX-880 (trial part A), while the rest, enrolled sequentially (part B), were each administered the full target dose of VX-880 given as a single infusion.
Induction with anti-thymocyte globulin and maintenance immunosuppressants, tacrolimus/sirolimus, was used to protect the cells from the recipient’s immune system. After the infusion, all six participants had C-peptide production, reduction in A1c despite reduced insulin use, and no severe hypoglycemia episodes from day 90 onwards.
Both participants with at least a year of follow-up met the criteria for the primary endpoint of A1c less than 7% with no severe hypoglycemic episodes. The first participant had an A1c of 5.3% at month 21, and the second 6.0% at 12 months. Both had sustained glucose-responsive insulin production with a mixed-meal tolerance test and exceeded the ADA target of more than 70% time-in blood glucose range assessed with continuous glucose monitoring.
Safety: No major concerns thus far
Among all six, adverse events included elevations in the liver enzyme transaminase, occurring shortly after VX-880 infusion that were transient and resolved. No serious adverse events were considered related to the therapy.
Regarding safety, Dr. Nostro said, “With this trial, I have no concerns, because they’re using immunosuppression, so should anything go bad, you remove immunosuppression and the cells would be destroyed by the immune system. So it’s a perfect trial in a way.”
However, she noted, “Moving forward, as we develop something that will be genetically modified ... I think this is the future, because if you’re going to treat people with type 1 diabetes, we have to eliminate the immune suppression. I think the concern would be making sure the genetically modified cells are safe.”
Dr. Nostro, who gave an introductory presentation at the beginning of the symposium where the VX-880 data were presented, explained that in a current trial of genetically modified cells, “they’re placing the product inside a device so that the cells would be retrievable. It might not be perfect, but at least it’s going to tell us whether the genetically modified product is safe, which I think is what we need to use.”
In her talk, Dr. Nostro also summarized ongoing work in this field involving efforts to improve the generation of stem cell–derived islets with no “off target” non-beta cells to ensure consistency, optimization of engraftment, and elimination of immunosuppression. “[VX-880] is the beginning. This is the first product that’s going to be in the clinic, but I can imagine how 5, 10 years from now we will have different and more enhanced solutions for type 1 diabetes and who knows, maybe even for type 2.”
Based on the data so far, the VX-880 trial is now moving to part C, in which 10 concurrently enrolled participants will receive the full target dose of the product. The trial, previously exclusively in the United States, has now expanded to additional sites in Norway, Switzerland, and the Netherlands.
The study was funded by Vertex. Dr. Reichman is on advisory boards for Vertex and Sernova. Dr. Nostro was a consultant for Sigilon Therapeutics from 2018-2022, currently receives research support from Universal Cells, and has a patent licensed to Sernova.
A version of this article originally appeared on Medscape.com.
SAN DIEGO – An investigational allogeneic stem cell–derived pancreatic islet cell replacement therapy (VX-880, Vertex Pharmaceuticals) continues to show promise as a treatment for type 1 diabetes, according to the latest data, from six patients thus far.
Two of the six are insulin-independent beyond 1 year after receiving the VX-880 infusions, and three others who received them more recently are on a similar trajectory. One dropped out because of reasons unrelated to the therapy. The remaining five are continuing to receive immunosuppressive treatment to prevent rejection of the islets. The six all had undetectable insulin secretion, impaired hypoglycemic awareness, and severe hypoglycemia as the criterion to enter the phase 1/2 study.
“These new findings demonstrate the potential of stem cell–derived islets as a future treatment for patients with type 1 diabetes, signaling a new era that could potentially remove the need for exogenously administered insulin to achieve glycemic control,” said lead investigator Trevor W. Reichman, MD, PhD, surgical director of Pancreas and Islet Cell Transplantation at the University of Toronto.
Dr. Reichman presented the data at the annual scientific sessions of the American Diabetes Association, as an update to the report of the first two patients at last year’s ADA meeting. “We are hopeful that this first-of-its-kind research could be a game-changer for the treatment of type 1 diabetes,” he emphasized.
Co-investigator Maria Cristina Nostro, PhD, senior scientist at McEwen Stem Cell Institute, Toronto, told this news organization: “The clinical trial data are extremely exciting ... I think what was very beautiful is the glucose tolerance test where the insulin secretion was almost like a person without type 1 diabetes. For someone who is in the lab doing basic science research ... all the work we’ve put into this, it’s a labor of love. We’ve been trying to generate the cells for so long, and now to see this, it’s fantastic.”
Two meet primary endpoint, three more on the right path
The six patients had a mean age of 44 years and mean 23 years’ diabetes duration. Three each were male and female. Their mean baseline A1c was 8.1%, and fasting C-peptide was undetectable. They had experienced a mean of 3.3 severe hypoglycemia episodes in the year prior to receiving the infusion, which was delivered to the portal vein similarly to the procedure with cadaveric donor islets, Dr. Reichman said.
The first two patients, including the one who dropped out, received half target doses of VX-880 (trial part A), while the rest, enrolled sequentially (part B), were each administered the full target dose of VX-880 given as a single infusion.
Induction with anti-thymocyte globulin and maintenance immunosuppressants, tacrolimus/sirolimus, was used to protect the cells from the recipient’s immune system. After the infusion, all six participants had C-peptide production, reduction in A1c despite reduced insulin use, and no severe hypoglycemia episodes from day 90 onwards.
Both participants with at least a year of follow-up met the criteria for the primary endpoint of A1c less than 7% with no severe hypoglycemic episodes. The first participant had an A1c of 5.3% at month 21, and the second 6.0% at 12 months. Both had sustained glucose-responsive insulin production with a mixed-meal tolerance test and exceeded the ADA target of more than 70% time-in blood glucose range assessed with continuous glucose monitoring.
Safety: No major concerns thus far
Among all six, adverse events included elevations in the liver enzyme transaminase, occurring shortly after VX-880 infusion that were transient and resolved. No serious adverse events were considered related to the therapy.
Regarding safety, Dr. Nostro said, “With this trial, I have no concerns, because they’re using immunosuppression, so should anything go bad, you remove immunosuppression and the cells would be destroyed by the immune system. So it’s a perfect trial in a way.”
However, she noted, “Moving forward, as we develop something that will be genetically modified ... I think this is the future, because if you’re going to treat people with type 1 diabetes, we have to eliminate the immune suppression. I think the concern would be making sure the genetically modified cells are safe.”
Dr. Nostro, who gave an introductory presentation at the beginning of the symposium where the VX-880 data were presented, explained that in a current trial of genetically modified cells, “they’re placing the product inside a device so that the cells would be retrievable. It might not be perfect, but at least it’s going to tell us whether the genetically modified product is safe, which I think is what we need to use.”
In her talk, Dr. Nostro also summarized ongoing work in this field involving efforts to improve the generation of stem cell–derived islets with no “off target” non-beta cells to ensure consistency, optimization of engraftment, and elimination of immunosuppression. “[VX-880] is the beginning. This is the first product that’s going to be in the clinic, but I can imagine how 5, 10 years from now we will have different and more enhanced solutions for type 1 diabetes and who knows, maybe even for type 2.”
Based on the data so far, the VX-880 trial is now moving to part C, in which 10 concurrently enrolled participants will receive the full target dose of the product. The trial, previously exclusively in the United States, has now expanded to additional sites in Norway, Switzerland, and the Netherlands.
The study was funded by Vertex. Dr. Reichman is on advisory boards for Vertex and Sernova. Dr. Nostro was a consultant for Sigilon Therapeutics from 2018-2022, currently receives research support from Universal Cells, and has a patent licensed to Sernova.
A version of this article originally appeared on Medscape.com.
SAN DIEGO – An investigational allogeneic stem cell–derived pancreatic islet cell replacement therapy (VX-880, Vertex Pharmaceuticals) continues to show promise as a treatment for type 1 diabetes, according to the latest data, from six patients thus far.
Two of the six are insulin-independent beyond 1 year after receiving the VX-880 infusions, and three others who received them more recently are on a similar trajectory. One dropped out because of reasons unrelated to the therapy. The remaining five are continuing to receive immunosuppressive treatment to prevent rejection of the islets. The six all had undetectable insulin secretion, impaired hypoglycemic awareness, and severe hypoglycemia as the criterion to enter the phase 1/2 study.
“These new findings demonstrate the potential of stem cell–derived islets as a future treatment for patients with type 1 diabetes, signaling a new era that could potentially remove the need for exogenously administered insulin to achieve glycemic control,” said lead investigator Trevor W. Reichman, MD, PhD, surgical director of Pancreas and Islet Cell Transplantation at the University of Toronto.
Dr. Reichman presented the data at the annual scientific sessions of the American Diabetes Association, as an update to the report of the first two patients at last year’s ADA meeting. “We are hopeful that this first-of-its-kind research could be a game-changer for the treatment of type 1 diabetes,” he emphasized.
Co-investigator Maria Cristina Nostro, PhD, senior scientist at McEwen Stem Cell Institute, Toronto, told this news organization: “The clinical trial data are extremely exciting ... I think what was very beautiful is the glucose tolerance test where the insulin secretion was almost like a person without type 1 diabetes. For someone who is in the lab doing basic science research ... all the work we’ve put into this, it’s a labor of love. We’ve been trying to generate the cells for so long, and now to see this, it’s fantastic.”
Two meet primary endpoint, three more on the right path
The six patients had a mean age of 44 years and mean 23 years’ diabetes duration. Three each were male and female. Their mean baseline A1c was 8.1%, and fasting C-peptide was undetectable. They had experienced a mean of 3.3 severe hypoglycemia episodes in the year prior to receiving the infusion, which was delivered to the portal vein similarly to the procedure with cadaveric donor islets, Dr. Reichman said.
The first two patients, including the one who dropped out, received half target doses of VX-880 (trial part A), while the rest, enrolled sequentially (part B), were each administered the full target dose of VX-880 given as a single infusion.
Induction with anti-thymocyte globulin and maintenance immunosuppressants, tacrolimus/sirolimus, was used to protect the cells from the recipient’s immune system. After the infusion, all six participants had C-peptide production, reduction in A1c despite reduced insulin use, and no severe hypoglycemia episodes from day 90 onwards.
Both participants with at least a year of follow-up met the criteria for the primary endpoint of A1c less than 7% with no severe hypoglycemic episodes. The first participant had an A1c of 5.3% at month 21, and the second 6.0% at 12 months. Both had sustained glucose-responsive insulin production with a mixed-meal tolerance test and exceeded the ADA target of more than 70% time-in blood glucose range assessed with continuous glucose monitoring.
Safety: No major concerns thus far
Among all six, adverse events included elevations in the liver enzyme transaminase, occurring shortly after VX-880 infusion that were transient and resolved. No serious adverse events were considered related to the therapy.
Regarding safety, Dr. Nostro said, “With this trial, I have no concerns, because they’re using immunosuppression, so should anything go bad, you remove immunosuppression and the cells would be destroyed by the immune system. So it’s a perfect trial in a way.”
However, she noted, “Moving forward, as we develop something that will be genetically modified ... I think this is the future, because if you’re going to treat people with type 1 diabetes, we have to eliminate the immune suppression. I think the concern would be making sure the genetically modified cells are safe.”
Dr. Nostro, who gave an introductory presentation at the beginning of the symposium where the VX-880 data were presented, explained that in a current trial of genetically modified cells, “they’re placing the product inside a device so that the cells would be retrievable. It might not be perfect, but at least it’s going to tell us whether the genetically modified product is safe, which I think is what we need to use.”
In her talk, Dr. Nostro also summarized ongoing work in this field involving efforts to improve the generation of stem cell–derived islets with no “off target” non-beta cells to ensure consistency, optimization of engraftment, and elimination of immunosuppression. “[VX-880] is the beginning. This is the first product that’s going to be in the clinic, but I can imagine how 5, 10 years from now we will have different and more enhanced solutions for type 1 diabetes and who knows, maybe even for type 2.”
Based on the data so far, the VX-880 trial is now moving to part C, in which 10 concurrently enrolled participants will receive the full target dose of the product. The trial, previously exclusively in the United States, has now expanded to additional sites in Norway, Switzerland, and the Netherlands.
The study was funded by Vertex. Dr. Reichman is on advisory boards for Vertex and Sernova. Dr. Nostro was a consultant for Sigilon Therapeutics from 2018-2022, currently receives research support from Universal Cells, and has a patent licensed to Sernova.
A version of this article originally appeared on Medscape.com.
AT ADA 2023
FDA OKs pancreatic islet cell therapy for type 1 diabetes
The Food and Drug Administration has approved donislecel (Lantidra, CellTrans), a pancreatic islet cell therapy developed from cadaver donors, for the treatment of people with type 1 diabetes who are unable to achieve target glucose levels owing to severe hypoglycemic episodes.
The product is given as a single infusion via the hepatic portal vein into the liver. A second infusion is given if necessary. Immunosuppression is required to maintain cell viability, just as it is required to support a transplanted kidney or other organ, as these all represent “foreign” tissues to the recipient.
“Today’s approval, the first-ever cell therapy to treat patients with type 1 diabetes, provides individuals living with type 1 diabetes and recurrent severe hypoglycemia an additional treatment option to help achieve target blood glucose levels,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, in an FDA statement.
The product was approved despite concerns from the American Society of Transplant Surgeons, the American Society of Transplantation, and an organization of more than 50 transplant surgeons – the Islets for U.S. Collaborative – whose members argue that cadaver-derived (allogeneic) pancreatic islets should be regulated as transplanted organs rather than as biologic drugs, as is done in many other parts of the world.
Lantidra differs from stem cell therapy being developed by Vertex Pharmaceuticals. In the latter, beta cells are grown from allogeneic stem cells using a proprietary technology. So far, six patients have received the therapy, and it has been successful in all of them to varying degrees, as reported at last week’s American Diabetes Association meeting. So while this is a promising technology, with talk of a “cure” for type 1 diabetes, it’s important to remember that this is very early in the development phase, says Anne Peters, MD, of the University of California, Los Angeles.
Approval based on small studies, with adverse events
The approval of Lantidra, following a 12-4 vote in favor by the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee in April 2021, was based on two nonrandomized, single-arm studies that included a total of 30 individuals with type 1 diabetes who had hypoglycemic unawareness and who received between one and three infusions of donislecel.
Insulin independence was achieved at 1 year by 21 participants; 11 were still insulin independent at 5 years, and 10 remained so more than 5 years. Five participants were unable to discontinue insulin treatment at all.
Adverse events included nausea, fatigue, anemia, diarrhea, and abdominal pain. Most of the participants experienced at least one serious adverse reaction related to the method of infusion and/or the use of immunosuppression. Some of these reactions required discontinuation of the immunosuppressive medications, resulting in the loss of islet cell function and return to insulin dependence.
“These adverse events should be considered when assessing the benefits and risks of Lantidra for each patient. Lantidra is approved with patient-directed labeling to inform patients with type 1 diabetes about benefits and risks of Lantidra,” according to the FDA statement.
U.S. transplant physicians had expressed concern, bill introduced
The transplant surgery organizations had written letters to the FDA, as well as to several other government agencies, to ask that the regulatory framework for Lantidra be shifted from the FDA to the Organ Procurement and Transplantation Network and the United Network for Organ Sharing.
They also wrote to members of Congress. On June 22, 2023, U.S. Senators Mike Lee (R-UT), Ted Budd (R-NC), and Marsha Blackburn (R-TN) introduced the Islet Transplantation Bill, which would shift the regulatory framework for cadaveric islets from that of biologic drugs to transplanted organs.
Asked for comment, Piotr Witkowski, MD, PhD, the leader of the Islets for U.S. Collaborative, told this news organization: “We were really happy about the introduction of the islet bill. Now, we’re concerned about negative downstream effects of granting a licence to a private company for distribution of the cadaveric islets.”
During the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee’s discussion in 2021, several panel members noted that the target patient population for this treatment with the current indication will likely be smaller today than it was when the two studies were initiated, in 2004 and 2007, given current automated diabetes technology – such as insulin pumps, continuous glucose monitors, and hybrid closed-loop systems in which the two are linked together as a so-called artificial pancreas – that reduces hypoglycemia risk.
A version of this article originally appeared on Medscape.com.
The Food and Drug Administration has approved donislecel (Lantidra, CellTrans), a pancreatic islet cell therapy developed from cadaver donors, for the treatment of people with type 1 diabetes who are unable to achieve target glucose levels owing to severe hypoglycemic episodes.
The product is given as a single infusion via the hepatic portal vein into the liver. A second infusion is given if necessary. Immunosuppression is required to maintain cell viability, just as it is required to support a transplanted kidney or other organ, as these all represent “foreign” tissues to the recipient.
“Today’s approval, the first-ever cell therapy to treat patients with type 1 diabetes, provides individuals living with type 1 diabetes and recurrent severe hypoglycemia an additional treatment option to help achieve target blood glucose levels,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, in an FDA statement.
The product was approved despite concerns from the American Society of Transplant Surgeons, the American Society of Transplantation, and an organization of more than 50 transplant surgeons – the Islets for U.S. Collaborative – whose members argue that cadaver-derived (allogeneic) pancreatic islets should be regulated as transplanted organs rather than as biologic drugs, as is done in many other parts of the world.
Lantidra differs from stem cell therapy being developed by Vertex Pharmaceuticals. In the latter, beta cells are grown from allogeneic stem cells using a proprietary technology. So far, six patients have received the therapy, and it has been successful in all of them to varying degrees, as reported at last week’s American Diabetes Association meeting. So while this is a promising technology, with talk of a “cure” for type 1 diabetes, it’s important to remember that this is very early in the development phase, says Anne Peters, MD, of the University of California, Los Angeles.
Approval based on small studies, with adverse events
The approval of Lantidra, following a 12-4 vote in favor by the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee in April 2021, was based on two nonrandomized, single-arm studies that included a total of 30 individuals with type 1 diabetes who had hypoglycemic unawareness and who received between one and three infusions of donislecel.
Insulin independence was achieved at 1 year by 21 participants; 11 were still insulin independent at 5 years, and 10 remained so more than 5 years. Five participants were unable to discontinue insulin treatment at all.
Adverse events included nausea, fatigue, anemia, diarrhea, and abdominal pain. Most of the participants experienced at least one serious adverse reaction related to the method of infusion and/or the use of immunosuppression. Some of these reactions required discontinuation of the immunosuppressive medications, resulting in the loss of islet cell function and return to insulin dependence.
“These adverse events should be considered when assessing the benefits and risks of Lantidra for each patient. Lantidra is approved with patient-directed labeling to inform patients with type 1 diabetes about benefits and risks of Lantidra,” according to the FDA statement.
U.S. transplant physicians had expressed concern, bill introduced
The transplant surgery organizations had written letters to the FDA, as well as to several other government agencies, to ask that the regulatory framework for Lantidra be shifted from the FDA to the Organ Procurement and Transplantation Network and the United Network for Organ Sharing.
They also wrote to members of Congress. On June 22, 2023, U.S. Senators Mike Lee (R-UT), Ted Budd (R-NC), and Marsha Blackburn (R-TN) introduced the Islet Transplantation Bill, which would shift the regulatory framework for cadaveric islets from that of biologic drugs to transplanted organs.
Asked for comment, Piotr Witkowski, MD, PhD, the leader of the Islets for U.S. Collaborative, told this news organization: “We were really happy about the introduction of the islet bill. Now, we’re concerned about negative downstream effects of granting a licence to a private company for distribution of the cadaveric islets.”
During the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee’s discussion in 2021, several panel members noted that the target patient population for this treatment with the current indication will likely be smaller today than it was when the two studies were initiated, in 2004 and 2007, given current automated diabetes technology – such as insulin pumps, continuous glucose monitors, and hybrid closed-loop systems in which the two are linked together as a so-called artificial pancreas – that reduces hypoglycemia risk.
A version of this article originally appeared on Medscape.com.
The Food and Drug Administration has approved donislecel (Lantidra, CellTrans), a pancreatic islet cell therapy developed from cadaver donors, for the treatment of people with type 1 diabetes who are unable to achieve target glucose levels owing to severe hypoglycemic episodes.
The product is given as a single infusion via the hepatic portal vein into the liver. A second infusion is given if necessary. Immunosuppression is required to maintain cell viability, just as it is required to support a transplanted kidney or other organ, as these all represent “foreign” tissues to the recipient.
“Today’s approval, the first-ever cell therapy to treat patients with type 1 diabetes, provides individuals living with type 1 diabetes and recurrent severe hypoglycemia an additional treatment option to help achieve target blood glucose levels,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, in an FDA statement.
The product was approved despite concerns from the American Society of Transplant Surgeons, the American Society of Transplantation, and an organization of more than 50 transplant surgeons – the Islets for U.S. Collaborative – whose members argue that cadaver-derived (allogeneic) pancreatic islets should be regulated as transplanted organs rather than as biologic drugs, as is done in many other parts of the world.
Lantidra differs from stem cell therapy being developed by Vertex Pharmaceuticals. In the latter, beta cells are grown from allogeneic stem cells using a proprietary technology. So far, six patients have received the therapy, and it has been successful in all of them to varying degrees, as reported at last week’s American Diabetes Association meeting. So while this is a promising technology, with talk of a “cure” for type 1 diabetes, it’s important to remember that this is very early in the development phase, says Anne Peters, MD, of the University of California, Los Angeles.
Approval based on small studies, with adverse events
The approval of Lantidra, following a 12-4 vote in favor by the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee in April 2021, was based on two nonrandomized, single-arm studies that included a total of 30 individuals with type 1 diabetes who had hypoglycemic unawareness and who received between one and three infusions of donislecel.
Insulin independence was achieved at 1 year by 21 participants; 11 were still insulin independent at 5 years, and 10 remained so more than 5 years. Five participants were unable to discontinue insulin treatment at all.
Adverse events included nausea, fatigue, anemia, diarrhea, and abdominal pain. Most of the participants experienced at least one serious adverse reaction related to the method of infusion and/or the use of immunosuppression. Some of these reactions required discontinuation of the immunosuppressive medications, resulting in the loss of islet cell function and return to insulin dependence.
“These adverse events should be considered when assessing the benefits and risks of Lantidra for each patient. Lantidra is approved with patient-directed labeling to inform patients with type 1 diabetes about benefits and risks of Lantidra,” according to the FDA statement.
U.S. transplant physicians had expressed concern, bill introduced
The transplant surgery organizations had written letters to the FDA, as well as to several other government agencies, to ask that the regulatory framework for Lantidra be shifted from the FDA to the Organ Procurement and Transplantation Network and the United Network for Organ Sharing.
They also wrote to members of Congress. On June 22, 2023, U.S. Senators Mike Lee (R-UT), Ted Budd (R-NC), and Marsha Blackburn (R-TN) introduced the Islet Transplantation Bill, which would shift the regulatory framework for cadaveric islets from that of biologic drugs to transplanted organs.
Asked for comment, Piotr Witkowski, MD, PhD, the leader of the Islets for U.S. Collaborative, told this news organization: “We were really happy about the introduction of the islet bill. Now, we’re concerned about negative downstream effects of granting a licence to a private company for distribution of the cadaveric islets.”
During the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee’s discussion in 2021, several panel members noted that the target patient population for this treatment with the current indication will likely be smaller today than it was when the two studies were initiated, in 2004 and 2007, given current automated diabetes technology – such as insulin pumps, continuous glucose monitors, and hybrid closed-loop systems in which the two are linked together as a so-called artificial pancreas – that reduces hypoglycemia risk.
A version of this article originally appeared on Medscape.com.