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Patients with higher HbA1c levels face greater risk for diabetic ketoacidosis
LOS ANGELES – results from a registry study have demonstrated.
The findings come from an analysis of the 2016-2017 Type 1 Diabetes Exchange Clinic Registry dataset that researchers, led by Carol Wysham, MD, presented at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists.
“This study is unique in that we have stratified patients based on A1c, and identified factors and patient characteristics associated with a greater risk of DKA as glycemic control diminishes,” Dr. Wysham, an endocrinologist at MultiCare Rockwood Clinic Diabetes & Endocrinology Center in Spokane, Wash., said in advance of the meeting. “Multiple interrelated factors, such as lower levels of education and household income, relationship status, access to private health insurance, being younger, and smoking, all affect a patient’s ability to properly manage insulin dosing and are associated with a higher risk of DKA. Health care providers should continue to monitor and educate all patients on the risk factors associated with developing DKA, and be vigilant in patients with an A1c of more than 9%.”
Dr. Wysham and her colleagues conducted a cross-sectional analysis of 6,242 patients in the registry. They examined associations between patient characteristics and treatment patterns with the occurrence of a DKA event in three categories of HbA1c: 7% to less than 8%, 8% to less than 9%, and 9% or greater. The researchers used chi-square or Fisher exact tests to compare DKA and non-DKA groups for categorical variables and t tests to compare continuous variables.
Of the 6,242 patients, 43% had an HbA1c from 7% to less than 8% (cohort 1), 31% had an HbA1c of 8% to less than 9% (cohort 2), and 30% had an HbA1c of 9% or greater (cohort 3). In all, 269 patients reported a DKA event. In addition, 1.7% of those in cohort 1 had a DKA episode versus 2.3% of those in cohort 2 and 9.5% of those in cohort 3.
In patients in cohort 1, the researchers observed no significant associations between individual patient demographic, socioeconomic, or treatment patterns and DKA incidence. In patients in cohort 2, race, marital status, insurance coverage, and annual household income were significantly associated with DKA incidence (P less than .01). In patients in cohort 3, DKA incidence was significantly associated with the same patterns as those in cohort 2, with the addition of age, type 1 diabetes duration, sex, education level, body mass index, and insulin delivery method (P less than .01).
On adjusted multivariate analysis, the researchers observed no significant associations between the factors studied and DKA in patients in cohort 2. In patients in cohort 3, only household income, smoking status, body mass index, and insulin delivery method (injection) were associated with DKA.
Dr. Wysham said she was surprised to learn that the patient characteristics and socioeconomic factors associated with DKA in patients with an HbA1c of more than 9% start to become less significant risk factors as patients achieved better glycemic control.
“Also, in the past, insulin pump users tended to have higher rates of DKA, compared with patients taking multiple daily insulin injections,” she said. “That phenomenon no longer seems to apply, and in this dataset, patients with an HbA1c of more than 9% and who were taking multiple daily injections had significantly higher risk of DKA than did pump users. Insulin delivery method was not a contributing factor to DKA risk at all in patients with an HbA1c of less than 9%.”
Dr. Wysham acknowledged certain limitations of the analysis, including the fact that the registry data “are collected from patients treated at diabetes centers of excellence and may not reflect the population as a whole. Data could have been collected from medical records and/or self-reported questionnaires from patients. Self-reported data are subjective and are limited to the patient’s own recollections.”
Dr. Wysham disclosed that she has received honoraria for advising, consulting, and/or speaking from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Dexcom, Novo Nordisk, and Sanofi. She also disclosed having received research funding from Mylan and Novo Nordisk that went to her institution.
LOS ANGELES – results from a registry study have demonstrated.
The findings come from an analysis of the 2016-2017 Type 1 Diabetes Exchange Clinic Registry dataset that researchers, led by Carol Wysham, MD, presented at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists.
“This study is unique in that we have stratified patients based on A1c, and identified factors and patient characteristics associated with a greater risk of DKA as glycemic control diminishes,” Dr. Wysham, an endocrinologist at MultiCare Rockwood Clinic Diabetes & Endocrinology Center in Spokane, Wash., said in advance of the meeting. “Multiple interrelated factors, such as lower levels of education and household income, relationship status, access to private health insurance, being younger, and smoking, all affect a patient’s ability to properly manage insulin dosing and are associated with a higher risk of DKA. Health care providers should continue to monitor and educate all patients on the risk factors associated with developing DKA, and be vigilant in patients with an A1c of more than 9%.”
Dr. Wysham and her colleagues conducted a cross-sectional analysis of 6,242 patients in the registry. They examined associations between patient characteristics and treatment patterns with the occurrence of a DKA event in three categories of HbA1c: 7% to less than 8%, 8% to less than 9%, and 9% or greater. The researchers used chi-square or Fisher exact tests to compare DKA and non-DKA groups for categorical variables and t tests to compare continuous variables.
Of the 6,242 patients, 43% had an HbA1c from 7% to less than 8% (cohort 1), 31% had an HbA1c of 8% to less than 9% (cohort 2), and 30% had an HbA1c of 9% or greater (cohort 3). In all, 269 patients reported a DKA event. In addition, 1.7% of those in cohort 1 had a DKA episode versus 2.3% of those in cohort 2 and 9.5% of those in cohort 3.
In patients in cohort 1, the researchers observed no significant associations between individual patient demographic, socioeconomic, or treatment patterns and DKA incidence. In patients in cohort 2, race, marital status, insurance coverage, and annual household income were significantly associated with DKA incidence (P less than .01). In patients in cohort 3, DKA incidence was significantly associated with the same patterns as those in cohort 2, with the addition of age, type 1 diabetes duration, sex, education level, body mass index, and insulin delivery method (P less than .01).
On adjusted multivariate analysis, the researchers observed no significant associations between the factors studied and DKA in patients in cohort 2. In patients in cohort 3, only household income, smoking status, body mass index, and insulin delivery method (injection) were associated with DKA.
Dr. Wysham said she was surprised to learn that the patient characteristics and socioeconomic factors associated with DKA in patients with an HbA1c of more than 9% start to become less significant risk factors as patients achieved better glycemic control.
“Also, in the past, insulin pump users tended to have higher rates of DKA, compared with patients taking multiple daily insulin injections,” she said. “That phenomenon no longer seems to apply, and in this dataset, patients with an HbA1c of more than 9% and who were taking multiple daily injections had significantly higher risk of DKA than did pump users. Insulin delivery method was not a contributing factor to DKA risk at all in patients with an HbA1c of less than 9%.”
Dr. Wysham acknowledged certain limitations of the analysis, including the fact that the registry data “are collected from patients treated at diabetes centers of excellence and may not reflect the population as a whole. Data could have been collected from medical records and/or self-reported questionnaires from patients. Self-reported data are subjective and are limited to the patient’s own recollections.”
Dr. Wysham disclosed that she has received honoraria for advising, consulting, and/or speaking from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Dexcom, Novo Nordisk, and Sanofi. She also disclosed having received research funding from Mylan and Novo Nordisk that went to her institution.
LOS ANGELES – results from a registry study have demonstrated.
The findings come from an analysis of the 2016-2017 Type 1 Diabetes Exchange Clinic Registry dataset that researchers, led by Carol Wysham, MD, presented at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists.
“This study is unique in that we have stratified patients based on A1c, and identified factors and patient characteristics associated with a greater risk of DKA as glycemic control diminishes,” Dr. Wysham, an endocrinologist at MultiCare Rockwood Clinic Diabetes & Endocrinology Center in Spokane, Wash., said in advance of the meeting. “Multiple interrelated factors, such as lower levels of education and household income, relationship status, access to private health insurance, being younger, and smoking, all affect a patient’s ability to properly manage insulin dosing and are associated with a higher risk of DKA. Health care providers should continue to monitor and educate all patients on the risk factors associated with developing DKA, and be vigilant in patients with an A1c of more than 9%.”
Dr. Wysham and her colleagues conducted a cross-sectional analysis of 6,242 patients in the registry. They examined associations between patient characteristics and treatment patterns with the occurrence of a DKA event in three categories of HbA1c: 7% to less than 8%, 8% to less than 9%, and 9% or greater. The researchers used chi-square or Fisher exact tests to compare DKA and non-DKA groups for categorical variables and t tests to compare continuous variables.
Of the 6,242 patients, 43% had an HbA1c from 7% to less than 8% (cohort 1), 31% had an HbA1c of 8% to less than 9% (cohort 2), and 30% had an HbA1c of 9% or greater (cohort 3). In all, 269 patients reported a DKA event. In addition, 1.7% of those in cohort 1 had a DKA episode versus 2.3% of those in cohort 2 and 9.5% of those in cohort 3.
In patients in cohort 1, the researchers observed no significant associations between individual patient demographic, socioeconomic, or treatment patterns and DKA incidence. In patients in cohort 2, race, marital status, insurance coverage, and annual household income were significantly associated with DKA incidence (P less than .01). In patients in cohort 3, DKA incidence was significantly associated with the same patterns as those in cohort 2, with the addition of age, type 1 diabetes duration, sex, education level, body mass index, and insulin delivery method (P less than .01).
On adjusted multivariate analysis, the researchers observed no significant associations between the factors studied and DKA in patients in cohort 2. In patients in cohort 3, only household income, smoking status, body mass index, and insulin delivery method (injection) were associated with DKA.
Dr. Wysham said she was surprised to learn that the patient characteristics and socioeconomic factors associated with DKA in patients with an HbA1c of more than 9% start to become less significant risk factors as patients achieved better glycemic control.
“Also, in the past, insulin pump users tended to have higher rates of DKA, compared with patients taking multiple daily insulin injections,” she said. “That phenomenon no longer seems to apply, and in this dataset, patients with an HbA1c of more than 9% and who were taking multiple daily injections had significantly higher risk of DKA than did pump users. Insulin delivery method was not a contributing factor to DKA risk at all in patients with an HbA1c of less than 9%.”
Dr. Wysham acknowledged certain limitations of the analysis, including the fact that the registry data “are collected from patients treated at diabetes centers of excellence and may not reflect the population as a whole. Data could have been collected from medical records and/or self-reported questionnaires from patients. Self-reported data are subjective and are limited to the patient’s own recollections.”
Dr. Wysham disclosed that she has received honoraria for advising, consulting, and/or speaking from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Dexcom, Novo Nordisk, and Sanofi. She also disclosed having received research funding from Mylan and Novo Nordisk that went to her institution.
REPORTING FROM AACE 2019
Use of levoketoconazole improved several clinical features of Cushing’s disease
LOS ANGELES – including acne, hirsutism, and peripheral edema, as did patient-reported quality of life and symptoms of depression.
The findings come from an analysis of secondary endpoints among patients enrolled in SONICS, an open-label, phase 3 study of levoketoconazole as a treatment for endogenous Cushing’s disease (CD) that enrolled 94 patients at centers in North America, Europe and the Middle East. An investigational cortisol synthesis inhibitor, levoketoconazole is being developed by Strongbridge Biopharma and is not yet approved by the Food and Drug Administration.
“Despite the availability of approved treatments, the medical needs in Cushing’s [disease] remain very high,” the study’s principal investigator, Maria Fleseriu, MD, FACE, said in an interview in advance of the annual scientific and clinical congress of the American Association of Clinical Endocrinologists, where the data were presented. “This study demonstrates that levoketoconazole has the potential to address several clinical features of Cushing’s, owing to its clinically translated novel mechanism of action to suppress both cortisol and androgen syntheses (the latter elevated in many women with CD). Interestingly, there was no evidence of clinically important free-T reduction in men, and more studies are needed to elucidate this mechanism.”
In SONICS, adults with confirmed CD and mean 24-hour urinary free-cortisol (mUFC) value at least 1.5 times the upper limit of normal were treated with levoketoconazole in three phases: 2- to 21-week dose-titration phase (150-600 mg BID, as needed, to target mUFC normalization); 6-month maintenance phase (primary endpoint); and 6-month extended evaluation phase. The end of maintenance phase findings that focused on reductions in mUFC and safety had been previously reported. The current analysis focused on secondary endpoints, including changes from baseline to end of maintenance in investigator-assessed CD clinical signs and symptoms (acne score [range: 0-44]; hirsutism score [women only; range: 0-36]; and peripheral edema score [range: 0-12]), and patient-reported outcomes of quality of life (Cushing QoL questionnaire score [range: 0-100]) and depression (Beck Depression Inventory II score [range: 0-63]). The researchers also assessed hormones including free testosterone levels, and they used paired t-tests to infer statistical significance of the mean changes from baseline to end of maintenance for all measures.
Of the 94 patients enrolled in SONICS, 77 entered the maintenance phase, said Dr. Fleseriu, professor of medicine and neurological surgery and director of the pituitary center at Oregon Health and Science University, Portland. The patients’ mean age was 44 years and mean baseline mUFC was 243.3 mcg/day; 82% of patients were female, and 96% were white. Between baseline and the end of maintenance, the researchers observed significant mean improvements in acne scores (from 2.8 to –1.8, respectively; P = .0063), hirsutism scores (women only, from 7.8 to –2.6; P = .0008), and peripheral edema scores (from 1.0 to –0.4; P = .0295). They also observed significant mean improvements in quality of life and depression scores between baseline and end of maintenance (P less than .0001 and P = .0043, respectively). Mean free-testosterone levels increased nonsignificantly between baseline and end of maintenance in men (from 5.1 to 5.8 ng/dL) yet decreased significantly in women (from 0.3 to 0.1 ng/dL; P less than 0.0001; reference). Overall, 33 patients (35%) discontinued taking levoketoconazole by the end of the maintenance phase. Twelve (13%) discontinued because of adverse events.
“I wasn’t necessarily surprised with any of the data in this poster as I had experience with the drug in clinical trials, but I was definitely pleased to see overall significant improvements in acne score, hirsutism score in women, and peripheral edema score,” Dr. Fleseriu said. “Those are benefits that could potentially increase long-term adherence to treatment and quality-of-life improvements, particularly in women. It’s also exciting to see that quality of life and depression improved in these patients as well.”
These types of patient-reported outcomes are so important to how our patients feel about their disease and should be more of a focus for us physicians; it’s important to look at efficacy, safety and patient reported outcomes when we decide for an individualized treatment for each patient,” she noted.
Dr. Fleseriu reported that she has received research funding for Oregon Health and Science University from Novartis, Millendo, and Strongbridge. She has also received scientific consulting fees from Novartis and Strongbridge.
LOS ANGELES – including acne, hirsutism, and peripheral edema, as did patient-reported quality of life and symptoms of depression.
The findings come from an analysis of secondary endpoints among patients enrolled in SONICS, an open-label, phase 3 study of levoketoconazole as a treatment for endogenous Cushing’s disease (CD) that enrolled 94 patients at centers in North America, Europe and the Middle East. An investigational cortisol synthesis inhibitor, levoketoconazole is being developed by Strongbridge Biopharma and is not yet approved by the Food and Drug Administration.
“Despite the availability of approved treatments, the medical needs in Cushing’s [disease] remain very high,” the study’s principal investigator, Maria Fleseriu, MD, FACE, said in an interview in advance of the annual scientific and clinical congress of the American Association of Clinical Endocrinologists, where the data were presented. “This study demonstrates that levoketoconazole has the potential to address several clinical features of Cushing’s, owing to its clinically translated novel mechanism of action to suppress both cortisol and androgen syntheses (the latter elevated in many women with CD). Interestingly, there was no evidence of clinically important free-T reduction in men, and more studies are needed to elucidate this mechanism.”
In SONICS, adults with confirmed CD and mean 24-hour urinary free-cortisol (mUFC) value at least 1.5 times the upper limit of normal were treated with levoketoconazole in three phases: 2- to 21-week dose-titration phase (150-600 mg BID, as needed, to target mUFC normalization); 6-month maintenance phase (primary endpoint); and 6-month extended evaluation phase. The end of maintenance phase findings that focused on reductions in mUFC and safety had been previously reported. The current analysis focused on secondary endpoints, including changes from baseline to end of maintenance in investigator-assessed CD clinical signs and symptoms (acne score [range: 0-44]; hirsutism score [women only; range: 0-36]; and peripheral edema score [range: 0-12]), and patient-reported outcomes of quality of life (Cushing QoL questionnaire score [range: 0-100]) and depression (Beck Depression Inventory II score [range: 0-63]). The researchers also assessed hormones including free testosterone levels, and they used paired t-tests to infer statistical significance of the mean changes from baseline to end of maintenance for all measures.
Of the 94 patients enrolled in SONICS, 77 entered the maintenance phase, said Dr. Fleseriu, professor of medicine and neurological surgery and director of the pituitary center at Oregon Health and Science University, Portland. The patients’ mean age was 44 years and mean baseline mUFC was 243.3 mcg/day; 82% of patients were female, and 96% were white. Between baseline and the end of maintenance, the researchers observed significant mean improvements in acne scores (from 2.8 to –1.8, respectively; P = .0063), hirsutism scores (women only, from 7.8 to –2.6; P = .0008), and peripheral edema scores (from 1.0 to –0.4; P = .0295). They also observed significant mean improvements in quality of life and depression scores between baseline and end of maintenance (P less than .0001 and P = .0043, respectively). Mean free-testosterone levels increased nonsignificantly between baseline and end of maintenance in men (from 5.1 to 5.8 ng/dL) yet decreased significantly in women (from 0.3 to 0.1 ng/dL; P less than 0.0001; reference). Overall, 33 patients (35%) discontinued taking levoketoconazole by the end of the maintenance phase. Twelve (13%) discontinued because of adverse events.
“I wasn’t necessarily surprised with any of the data in this poster as I had experience with the drug in clinical trials, but I was definitely pleased to see overall significant improvements in acne score, hirsutism score in women, and peripheral edema score,” Dr. Fleseriu said. “Those are benefits that could potentially increase long-term adherence to treatment and quality-of-life improvements, particularly in women. It’s also exciting to see that quality of life and depression improved in these patients as well.”
These types of patient-reported outcomes are so important to how our patients feel about their disease and should be more of a focus for us physicians; it’s important to look at efficacy, safety and patient reported outcomes when we decide for an individualized treatment for each patient,” she noted.
Dr. Fleseriu reported that she has received research funding for Oregon Health and Science University from Novartis, Millendo, and Strongbridge. She has also received scientific consulting fees from Novartis and Strongbridge.
LOS ANGELES – including acne, hirsutism, and peripheral edema, as did patient-reported quality of life and symptoms of depression.
The findings come from an analysis of secondary endpoints among patients enrolled in SONICS, an open-label, phase 3 study of levoketoconazole as a treatment for endogenous Cushing’s disease (CD) that enrolled 94 patients at centers in North America, Europe and the Middle East. An investigational cortisol synthesis inhibitor, levoketoconazole is being developed by Strongbridge Biopharma and is not yet approved by the Food and Drug Administration.
“Despite the availability of approved treatments, the medical needs in Cushing’s [disease] remain very high,” the study’s principal investigator, Maria Fleseriu, MD, FACE, said in an interview in advance of the annual scientific and clinical congress of the American Association of Clinical Endocrinologists, where the data were presented. “This study demonstrates that levoketoconazole has the potential to address several clinical features of Cushing’s, owing to its clinically translated novel mechanism of action to suppress both cortisol and androgen syntheses (the latter elevated in many women with CD). Interestingly, there was no evidence of clinically important free-T reduction in men, and more studies are needed to elucidate this mechanism.”
In SONICS, adults with confirmed CD and mean 24-hour urinary free-cortisol (mUFC) value at least 1.5 times the upper limit of normal were treated with levoketoconazole in three phases: 2- to 21-week dose-titration phase (150-600 mg BID, as needed, to target mUFC normalization); 6-month maintenance phase (primary endpoint); and 6-month extended evaluation phase. The end of maintenance phase findings that focused on reductions in mUFC and safety had been previously reported. The current analysis focused on secondary endpoints, including changes from baseline to end of maintenance in investigator-assessed CD clinical signs and symptoms (acne score [range: 0-44]; hirsutism score [women only; range: 0-36]; and peripheral edema score [range: 0-12]), and patient-reported outcomes of quality of life (Cushing QoL questionnaire score [range: 0-100]) and depression (Beck Depression Inventory II score [range: 0-63]). The researchers also assessed hormones including free testosterone levels, and they used paired t-tests to infer statistical significance of the mean changes from baseline to end of maintenance for all measures.
Of the 94 patients enrolled in SONICS, 77 entered the maintenance phase, said Dr. Fleseriu, professor of medicine and neurological surgery and director of the pituitary center at Oregon Health and Science University, Portland. The patients’ mean age was 44 years and mean baseline mUFC was 243.3 mcg/day; 82% of patients were female, and 96% were white. Between baseline and the end of maintenance, the researchers observed significant mean improvements in acne scores (from 2.8 to –1.8, respectively; P = .0063), hirsutism scores (women only, from 7.8 to –2.6; P = .0008), and peripheral edema scores (from 1.0 to –0.4; P = .0295). They also observed significant mean improvements in quality of life and depression scores between baseline and end of maintenance (P less than .0001 and P = .0043, respectively). Mean free-testosterone levels increased nonsignificantly between baseline and end of maintenance in men (from 5.1 to 5.8 ng/dL) yet decreased significantly in women (from 0.3 to 0.1 ng/dL; P less than 0.0001; reference). Overall, 33 patients (35%) discontinued taking levoketoconazole by the end of the maintenance phase. Twelve (13%) discontinued because of adverse events.
“I wasn’t necessarily surprised with any of the data in this poster as I had experience with the drug in clinical trials, but I was definitely pleased to see overall significant improvements in acne score, hirsutism score in women, and peripheral edema score,” Dr. Fleseriu said. “Those are benefits that could potentially increase long-term adherence to treatment and quality-of-life improvements, particularly in women. It’s also exciting to see that quality of life and depression improved in these patients as well.”
These types of patient-reported outcomes are so important to how our patients feel about their disease and should be more of a focus for us physicians; it’s important to look at efficacy, safety and patient reported outcomes when we decide for an individualized treatment for each patient,” she noted.
Dr. Fleseriu reported that she has received research funding for Oregon Health and Science University from Novartis, Millendo, and Strongbridge. She has also received scientific consulting fees from Novartis and Strongbridge.
REPORTING FROM AACE 2019
Key clinical point: Several clinical features of Cushing’s disease improved following 6 months of treatment with the investigational agent levoketoconazole.
Major finding: Between baseline and the end of maintenance, the researchers observed significant mean improvements in acne scores (from 2.8 to –1.8, respectively; P = .0063), hirsutism scores (women only, from 7.8 to –2.6; P = .0008), and peripheral edema scores (from 1.0 to –0.4; P = .0295).
Study details: An analysis of secondary endpoints among 77 patients enrolled in SONICS.
Disclosures: Dr. Fleseriu reported that she has received research funding for Oregon Health and Science University from Novartis, Millendo, and Strongbridge. She has also received scientific consulting fees from Novartis and Strongbridge.