Drug Therapy

Even on-time pneumococcal vaccines don’t completely protect children with asthma from developing invasive pneumococcal disease, a meta-analysis has determined.

Despite receiving pneumococcal valent 7, 10, or 13, children with asthma were still almost twice as likely to develop the disease as were children without asthma, Jose A. Castro-Rodriguez, MD, PhD, and colleagues reported in Pediatrics (2020 Jan. doi: 10.1542/peds.2019-1200). None of the studies included rates for those who received the pneumococcal polysaccharide vaccine (PPSV23).

“For the first time, this meta-analysis reveals 90% increased odds of invasive pneumococcal disease (IPD) among [vaccinated] children with asthma,” said Dr. Castro-Rodriguez, of Pontificia Universidad Católica de Chile, Santiago, and colleagues. “If confirmed, these findings will bear clinical and public health importance,” they noted, because guidelines now recommend PPSV23 after age 2 in children with asthma only if they’re treated with prolonged high-dose oral corticosteroids.

However, because the analysis comprised only four studies, the authors cautioned that the results aren’t enough to justify changes to practice recommendations.

Asthma treatment with inhaled corticosteroids (ICS) may be driving the increased risk, Dr. Castro-Rodriguez and his coauthors suggested. ICS deposition in the oropharynx could boost oropharyngeal candidiasis risk by weakening the mucosal immune response, the researchers noted. And that same process may be at work with Streptococcus pneumoniae.

A prior study found that children with asthma who received ICS for at least 1 month were almost four times more likely to have oropharyngeal colonization by S. pneumoniae as were those who didn’t get the drugs. Thus, a higher carrier rate of S. pneumoniae in the oropharynx, along with asthma’s impaired airway clearance, might increase the risk of pneumococcal diseases, the investigators explained.

Dr. Castro-Rodriguez and colleagues analyzed four studies with more than 4,000 cases and controls, and about 26 million person-years of follow-up.

Rates and risks of IPD in the four studies were as follows:

• Among those with IPD, 27% had asthma, with 18% of those without, an adjusted odds ratio (aOR) of 1.8.
• In a European of patients who received at least 3 doses of PCV7, IPD rates per 100,000 person-years for 5-year-olds were 11.6 for children with asthma and 7.3 for those without. For 5- to 17-year-olds with and without asthma, the rates were 2.3 and 1.6, respectively.
• In 2001, a Korean found an aOR of 2.08 for IPD in children with asthma, compared with those without. In 2010, the aOR was 3.26. No vaccine types were reported in the study.
• of IPD were 3.7 per 100,000 person-years for children with asthma, compared with 2.5 for healthy controls – an adjusted relative risk of 1.5.

The pooled estimate of the four studies revealed an aOR of 1.9 for IPD among children with asthma, compared with those without, Dr. Castro-Rodriguez and his team concluded.

None of the studies reported hospital admissions, mortality, length of hospital stay, intensive care admission, invasive respiratory support, or additional medication use.

One, however, did find asthma severity was significantly associated with increasing IPD treatment costs per 100,000 person-years: $72,581 for healthy controls, compared with $100,020 for children with mild asthma, $172,002 for moderate asthma, and $638,452 for severe asthma.

In addition, treating all-cause pneumonia was more expensive in children with asthma. For all-cause pneumonia, the researchers found that estimated costs per 100,000 person-years for mild, moderate, and severe asthma were $7.5 million, $14.6 million, and $46.8 million, respectively, compared with $1.7 million for healthy controls.

The authors had no relevant financial disclosures.

[email protected]

SOURCE: Castro-Rodriguez J et al. Pediatrics. 2020 Jan. doi: 10.1542/peds.2019-1200.

Even on-time pneumococcal vaccines don’t completely protect children with asthma from developing invasive pneumococcal disease, a meta-analysis has determined.

Despite receiving pneumococcal valent 7, 10, or 13, children with asthma were still almost twice as likely to develop the disease as were children without asthma, Jose A. Castro-Rodriguez, MD, PhD, and colleagues reported in Pediatrics (2020 Jan. doi: 10.1542/peds.2019-1200). None of the studies included rates for those who received the pneumococcal polysaccharide vaccine (PPSV23).

“For the first time, this meta-analysis reveals 90% increased odds of invasive pneumococcal disease (IPD) among [vaccinated] children with asthma,” said Dr. Castro-Rodriguez, of Pontificia Universidad Católica de Chile, Santiago, and colleagues. “If confirmed, these findings will bear clinical and public health importance,” they noted, because guidelines now recommend PPSV23 after age 2 in children with asthma only if they’re treated with prolonged high-dose oral corticosteroids.

However, because the analysis comprised only four studies, the authors cautioned that the results aren’t enough to justify changes to practice recommendations.

Asthma treatment with inhaled corticosteroids (ICS) may be driving the increased risk, Dr. Castro-Rodriguez and his coauthors suggested. ICS deposition in the oropharynx could boost oropharyngeal candidiasis risk by weakening the mucosal immune response, the researchers noted. And that same process may be at work with Streptococcus pneumoniae.

A prior study found that children with asthma who received ICS for at least 1 month were almost four times more likely to have oropharyngeal colonization by S. pneumoniae as were those who didn’t get the drugs. Thus, a higher carrier rate of S. pneumoniae in the oropharynx, along with asthma’s impaired airway clearance, might increase the risk of pneumococcal diseases, the investigators explained.

Dr. Castro-Rodriguez and colleagues analyzed four studies with more than 4,000 cases and controls, and about 26 million person-years of follow-up.

Rates and risks of IPD in the four studies were as follows:

• Among those with IPD, 27% had asthma, with 18% of those without, an adjusted odds ratio (aOR) of 1.8.
• In a European of patients who received at least 3 doses of PCV7, IPD rates per 100,000 person-years for 5-year-olds were 11.6 for children with asthma and 7.3 for those without. For 5- to 17-year-olds with and without asthma, the rates were 2.3 and 1.6, respectively.
• In 2001, a Korean found an aOR of 2.08 for IPD in children with asthma, compared with those without. In 2010, the aOR was 3.26. No vaccine types were reported in the study.
• of IPD were 3.7 per 100,000 person-years for children with asthma, compared with 2.5 for healthy controls – an adjusted relative risk of 1.5.

The pooled estimate of the four studies revealed an aOR of 1.9 for IPD among children with asthma, compared with those without, Dr. Castro-Rodriguez and his team concluded.

None of the studies reported hospital admissions, mortality, length of hospital stay, intensive care admission, invasive respiratory support, or additional medication use.

One, however, did find asthma severity was significantly associated with increasing IPD treatment costs per 100,000 person-years: $72,581 for healthy controls, compared with $100,020 for children with mild asthma, $172,002 for moderate asthma, and $638,452 for severe asthma.

In addition, treating all-cause pneumonia was more expensive in children with asthma. For all-cause pneumonia, the researchers found that estimated costs per 100,000 person-years for mild, moderate, and severe asthma were $7.5 million, $14.6 million, and $46.8 million, respectively, compared with $1.7 million for healthy controls.

The authors had no relevant financial disclosures.

[email protected]

SOURCE: Castro-Rodriguez J et al. Pediatrics. 2020 Jan. doi: 10.1542/peds.2019-1200.

Even on-time pneumococcal vaccines don’t completely protect children with asthma from developing invasive pneumococcal disease, a meta-analysis has determined.

Despite receiving pneumococcal valent 7, 10, or 13, children with asthma were still almost twice as likely to develop the disease as were children without asthma, Jose A. Castro-Rodriguez, MD, PhD, and colleagues reported in Pediatrics (2020 Jan. doi: 10.1542/peds.2019-1200). None of the studies included rates for those who received the pneumococcal polysaccharide vaccine (PPSV23).

“For the first time, this meta-analysis reveals 90% increased odds of invasive pneumococcal disease (IPD) among [vaccinated] children with asthma,” said Dr. Castro-Rodriguez, of Pontificia Universidad Católica de Chile, Santiago, and colleagues. “If confirmed, these findings will bear clinical and public health importance,” they noted, because guidelines now recommend PPSV23 after age 2 in children with asthma only if they’re treated with prolonged high-dose oral corticosteroids.

However, because the analysis comprised only four studies, the authors cautioned that the results aren’t enough to justify changes to practice recommendations.

Asthma treatment with inhaled corticosteroids (ICS) may be driving the increased risk, Dr. Castro-Rodriguez and his coauthors suggested. ICS deposition in the oropharynx could boost oropharyngeal candidiasis risk by weakening the mucosal immune response, the researchers noted. And that same process may be at work with Streptococcus pneumoniae.

A prior study found that children with asthma who received ICS for at least 1 month were almost four times more likely to have oropharyngeal colonization by S. pneumoniae as were those who didn’t get the drugs. Thus, a higher carrier rate of S. pneumoniae in the oropharynx, along with asthma’s impaired airway clearance, might increase the risk of pneumococcal diseases, the investigators explained.

Dr. Castro-Rodriguez and colleagues analyzed four studies with more than 4,000 cases and controls, and about 26 million person-years of follow-up.

Rates and risks of IPD in the four studies were as follows:

• Among those with IPD, 27% had asthma, with 18% of those without, an adjusted odds ratio (aOR) of 1.8.
• In a European of patients who received at least 3 doses of PCV7, IPD rates per 100,000 person-years for 5-year-olds were 11.6 for children with asthma and 7.3 for those without. For 5- to 17-year-olds with and without asthma, the rates were 2.3 and 1.6, respectively.
• In 2001, a Korean found an aOR of 2.08 for IPD in children with asthma, compared with those without. In 2010, the aOR was 3.26. No vaccine types were reported in the study.
• of IPD were 3.7 per 100,000 person-years for children with asthma, compared with 2.5 for healthy controls – an adjusted relative risk of 1.5.

The pooled estimate of the four studies revealed an aOR of 1.9 for IPD among children with asthma, compared with those without, Dr. Castro-Rodriguez and his team concluded.

None of the studies reported hospital admissions, mortality, length of hospital stay, intensive care admission, invasive respiratory support, or additional medication use.

One, however, did find asthma severity was significantly associated with increasing IPD treatment costs per 100,000 person-years: $72,581 for healthy controls, compared with $100,020 for children with mild asthma, $172,002 for moderate asthma, and $638,452 for severe asthma.

In addition, treating all-cause pneumonia was more expensive in children with asthma. For all-cause pneumonia, the researchers found that estimated costs per 100,000 person-years for mild, moderate, and severe asthma were $7.5 million, $14.6 million, and $46.8 million, respectively, compared with $1.7 million for healthy controls.

The authors had no relevant financial disclosures.

[email protected]

SOURCE: Castro-Rodriguez J et al. Pediatrics. 2020 Jan. doi: 10.1542/peds.2019-1200.

BALTIMORE – Monitoring children who have tuberous sclerosis with EEG and treating them with vigabatrin (Sabril) at the first sign of preseizure abnormalities, rather than the usual practice of no surveillance and waiting until they have seizures, prevents epilepsy and cognitive decline, according to European investigators.

M. Alexander Otto/MDedge News

Early surveillance is recommended and standard practice in Europe. That’s not the case in the United States, but might be someday pending the results of the PREVENT trial (Preventing Epilepsy Using Vigabatrin In Infants With Tuberous Sclerosis Complex), an ongoing, National Institute of Neurological Disorders and Stroke–funded study to confirm the European findings.

“We are trying to convince doctors” in the United States and other “countries to do this. If you are not convinced to do early treatment,” at least “do surveillance with EEG. You will diagnose epilepsy earlier, and treat earlier, and children will do much better,” said Sergiusz Jozwiak, MD, PhD, head of pediatric neurology at Warsaw Medical University and recipient of an award from the U.S. Tuberous Sclerosis Alliance for his pioneering work.

Some U.S. physicians are already doing preventive treatment, but it’s hit and miss. “We are talking about monitoring children below the age of 2 years,” when seizures are associated with cognitive decline, he noted at the annual meeting of the American Epilepsy Society.

Dr. Jozwiak presented a follow-up at the meeting to his 2011 investigation, the first prevention study in tuberous sclerosis. Fourteen infants diagnosed within 2 months of birth underwent video-EEG monitoring every 4-6 weeks until age 2 years and were treated with vigabatrin 100-150 mg/kg per day when multifocal epileptiform discharges – a sign of impending seizures – were detected. Outcomes were compared with infants treated traditionally, with no EEG monitoring and vigabatrin only after they seized.

The children are about 9 years old now; the median IQ in the prevention arm is 94 versus 46 in the control group (P less than .03). Seven of the 14 prevention children (50%) never had a clinical seizure, while all but 1 of 25 (96%) in the control arm did (P = .001). Six of 11 prevention children (55%) versus 4 of 24 in the control group (17%), were able to come off antiepileptic drugs altogether, with no seizures (P less than .03). The work was published shortly before the epilepsy meeting.

The original 2011 report, which had similarly favorable outcomes when the children were 2 years old, led directly to the EpiStop trial, conducted at 16 mostly European centers and also reported at the meeting. Dr. Jozwiak was the senior investigator.

The design was different; all of the infants had EEG monitoring every 4 weeks until month 6, then every 6 weeks until age 12 months, then every 2 months until age 2 years. At the first detection of multifocal epileptiform discharges, infants were randomized 1:1 to vigabatrin or to the control group, with further monitoring followed by vigabatrin at the first seizure on EEG or first clinical seizure. An additional group of children – the open-label arm – also had EEG monitoring, but when to start vigabatrin was left up to the study site.

M. Alexander Otto/MDedge News

Only 50 of the original 94 children completed the trial to the full 2 years; tuberous sclerosis comorbidities drove many of them out, said lead investigator Katarzyna Kotulska-Jozwiak, MD, PhD, head of neurology at Children’s Memorial Health Institute, Warsaw.

Even so, the 25 children treated preventively in the randomized and open-label cohorts were more than three times as likely to be seizure free at 2 years (P = .01), and 74% less likely to develop drug-resistant epilepsy (P = .013). None of the prevention children developed infantile spasms versus 10 controls (40%) treated at first clinical or EEG seizure.

The incidence of neurodevelopmental delay was 34%, and autism 33%, at 24 months, and did not differ between prevention and control subjects. It’s probably because even children in the control group benefited from EEG surveillance and early treatment, the investigators said.

Historically, the rate of intellectual disability with usual treatment is around 60%, Dr. Kotulska-Jozwiak noted.

Overall, Dr. Jozwiak said that European physicians are more comfortable using vigabatrin than U.S. doctors, where the drug hasn’t been on the market as long and carries a Food and Drug Administration boxed warning of visual impairment. Its indications in the United States include infantile spasms in children 1-24 months old.

Levetiracetam (Keppra) is another option, but it’s not as effective in tuberous sclerosis. The PREVENT trial is using vigabatrin, and some U.S. doctors “are changing their minds, but it takes time,” Dr. Jozwiak said.

He noted that TSC is increasingly being diagnosed in utero, which gives a leg up on early diagnosis and prevention. The giveaways are heart tumors on ECG and cortical tubers on fetal MRI.

Dr. Jozwiak thinks the prevention approach might also help in other early seizure disorders, such as Sturge-Weber syndrome.

The work was funded by the European Commission and Polish government. Dr. Jozwiak and Dr. Kotulska-Jozwiak didn’t have any disclosures.
 

[email protected]

SOURCES: Jozwiak S et al. AES 2019, Abstract 1.218; Kotulska-Jozwiak K et al. AES 2019, Abstract 2.121.

BALTIMORE – Monitoring children who have tuberous sclerosis with EEG and treating them with vigabatrin (Sabril) at the first sign of preseizure abnormalities, rather than the usual practice of no surveillance and waiting until they have seizures, prevents epilepsy and cognitive decline, according to European investigators.

M. Alexander Otto/MDedge News

Early surveillance is recommended and standard practice in Europe. That’s not the case in the United States, but might be someday pending the results of the PREVENT trial (Preventing Epilepsy Using Vigabatrin In Infants With Tuberous Sclerosis Complex), an ongoing, National Institute of Neurological Disorders and Stroke–funded study to confirm the European findings.

“We are trying to convince doctors” in the United States and other “countries to do this. If you are not convinced to do early treatment,” at least “do surveillance with EEG. You will diagnose epilepsy earlier, and treat earlier, and children will do much better,” said Sergiusz Jozwiak, MD, PhD, head of pediatric neurology at Warsaw Medical University and recipient of an award from the U.S. Tuberous Sclerosis Alliance for his pioneering work.

Some U.S. physicians are already doing preventive treatment, but it’s hit and miss. “We are talking about monitoring children below the age of 2 years,” when seizures are associated with cognitive decline, he noted at the annual meeting of the American Epilepsy Society.

Dr. Jozwiak presented a follow-up at the meeting to his 2011 investigation, the first prevention study in tuberous sclerosis. Fourteen infants diagnosed within 2 months of birth underwent video-EEG monitoring every 4-6 weeks until age 2 years and were treated with vigabatrin 100-150 mg/kg per day when multifocal epileptiform discharges – a sign of impending seizures – were detected. Outcomes were compared with infants treated traditionally, with no EEG monitoring and vigabatrin only after they seized.

The children are about 9 years old now; the median IQ in the prevention arm is 94 versus 46 in the control group (P less than .03). Seven of the 14 prevention children (50%) never had a clinical seizure, while all but 1 of 25 (96%) in the control arm did (P = .001). Six of 11 prevention children (55%) versus 4 of 24 in the control group (17%), were able to come off antiepileptic drugs altogether, with no seizures (P less than .03). The work was published shortly before the epilepsy meeting.

The original 2011 report, which had similarly favorable outcomes when the children were 2 years old, led directly to the EpiStop trial, conducted at 16 mostly European centers and also reported at the meeting. Dr. Jozwiak was the senior investigator.

The design was different; all of the infants had EEG monitoring every 4 weeks until month 6, then every 6 weeks until age 12 months, then every 2 months until age 2 years. At the first detection of multifocal epileptiform discharges, infants were randomized 1:1 to vigabatrin or to the control group, with further monitoring followed by vigabatrin at the first seizure on EEG or first clinical seizure. An additional group of children – the open-label arm – also had EEG monitoring, but when to start vigabatrin was left up to the study site.

M. Alexander Otto/MDedge News

Only 50 of the original 94 children completed the trial to the full 2 years; tuberous sclerosis comorbidities drove many of them out, said lead investigator Katarzyna Kotulska-Jozwiak, MD, PhD, head of neurology at Children’s Memorial Health Institute, Warsaw.

Even so, the 25 children treated preventively in the randomized and open-label cohorts were more than three times as likely to be seizure free at 2 years (P = .01), and 74% less likely to develop drug-resistant epilepsy (P = .013). None of the prevention children developed infantile spasms versus 10 controls (40%) treated at first clinical or EEG seizure.

The incidence of neurodevelopmental delay was 34%, and autism 33%, at 24 months, and did not differ between prevention and control subjects. It’s probably because even children in the control group benefited from EEG surveillance and early treatment, the investigators said.

Historically, the rate of intellectual disability with usual treatment is around 60%, Dr. Kotulska-Jozwiak noted.

Overall, Dr. Jozwiak said that European physicians are more comfortable using vigabatrin than U.S. doctors, where the drug hasn’t been on the market as long and carries a Food and Drug Administration boxed warning of visual impairment. Its indications in the United States include infantile spasms in children 1-24 months old.

Levetiracetam (Keppra) is another option, but it’s not as effective in tuberous sclerosis. The PREVENT trial is using vigabatrin, and some U.S. doctors “are changing their minds, but it takes time,” Dr. Jozwiak said.

He noted that TSC is increasingly being diagnosed in utero, which gives a leg up on early diagnosis and prevention. The giveaways are heart tumors on ECG and cortical tubers on fetal MRI.

Dr. Jozwiak thinks the prevention approach might also help in other early seizure disorders, such as Sturge-Weber syndrome.

The work was funded by the European Commission and Polish government. Dr. Jozwiak and Dr. Kotulska-Jozwiak didn’t have any disclosures.
 

[email protected]

SOURCES: Jozwiak S et al. AES 2019, Abstract 1.218; Kotulska-Jozwiak K et al. AES 2019, Abstract 2.121.

BALTIMORE – Monitoring children who have tuberous sclerosis with EEG and treating them with vigabatrin (Sabril) at the first sign of preseizure abnormalities, rather than the usual practice of no surveillance and waiting until they have seizures, prevents epilepsy and cognitive decline, according to European investigators.

M. Alexander Otto/MDedge News

Early surveillance is recommended and standard practice in Europe. That’s not the case in the United States, but might be someday pending the results of the PREVENT trial (Preventing Epilepsy Using Vigabatrin In Infants With Tuberous Sclerosis Complex), an ongoing, National Institute of Neurological Disorders and Stroke–funded study to confirm the European findings.

“We are trying to convince doctors” in the United States and other “countries to do this. If you are not convinced to do early treatment,” at least “do surveillance with EEG. You will diagnose epilepsy earlier, and treat earlier, and children will do much better,” said Sergiusz Jozwiak, MD, PhD, head of pediatric neurology at Warsaw Medical University and recipient of an award from the U.S. Tuberous Sclerosis Alliance for his pioneering work.

Some U.S. physicians are already doing preventive treatment, but it’s hit and miss. “We are talking about monitoring children below the age of 2 years,” when seizures are associated with cognitive decline, he noted at the annual meeting of the American Epilepsy Society.

Dr. Jozwiak presented a follow-up at the meeting to his 2011 investigation, the first prevention study in tuberous sclerosis. Fourteen infants diagnosed within 2 months of birth underwent video-EEG monitoring every 4-6 weeks until age 2 years and were treated with vigabatrin 100-150 mg/kg per day when multifocal epileptiform discharges – a sign of impending seizures – were detected. Outcomes were compared with infants treated traditionally, with no EEG monitoring and vigabatrin only after they seized.

The children are about 9 years old now; the median IQ in the prevention arm is 94 versus 46 in the control group (P less than .03). Seven of the 14 prevention children (50%) never had a clinical seizure, while all but 1 of 25 (96%) in the control arm did (P = .001). Six of 11 prevention children (55%) versus 4 of 24 in the control group (17%), were able to come off antiepileptic drugs altogether, with no seizures (P less than .03). The work was published shortly before the epilepsy meeting.

The original 2011 report, which had similarly favorable outcomes when the children were 2 years old, led directly to the EpiStop trial, conducted at 16 mostly European centers and also reported at the meeting. Dr. Jozwiak was the senior investigator.

The design was different; all of the infants had EEG monitoring every 4 weeks until month 6, then every 6 weeks until age 12 months, then every 2 months until age 2 years. At the first detection of multifocal epileptiform discharges, infants were randomized 1:1 to vigabatrin or to the control group, with further monitoring followed by vigabatrin at the first seizure on EEG or first clinical seizure. An additional group of children – the open-label arm – also had EEG monitoring, but when to start vigabatrin was left up to the study site.

M. Alexander Otto/MDedge News

Only 50 of the original 94 children completed the trial to the full 2 years; tuberous sclerosis comorbidities drove many of them out, said lead investigator Katarzyna Kotulska-Jozwiak, MD, PhD, head of neurology at Children’s Memorial Health Institute, Warsaw.

Even so, the 25 children treated preventively in the randomized and open-label cohorts were more than three times as likely to be seizure free at 2 years (P = .01), and 74% less likely to develop drug-resistant epilepsy (P = .013). None of the prevention children developed infantile spasms versus 10 controls (40%) treated at first clinical or EEG seizure.

The incidence of neurodevelopmental delay was 34%, and autism 33%, at 24 months, and did not differ between prevention and control subjects. It’s probably because even children in the control group benefited from EEG surveillance and early treatment, the investigators said.

Historically, the rate of intellectual disability with usual treatment is around 60%, Dr. Kotulska-Jozwiak noted.

Overall, Dr. Jozwiak said that European physicians are more comfortable using vigabatrin than U.S. doctors, where the drug hasn’t been on the market as long and carries a Food and Drug Administration boxed warning of visual impairment. Its indications in the United States include infantile spasms in children 1-24 months old.

Levetiracetam (Keppra) is another option, but it’s not as effective in tuberous sclerosis. The PREVENT trial is using vigabatrin, and some U.S. doctors “are changing their minds, but it takes time,” Dr. Jozwiak said.

He noted that TSC is increasingly being diagnosed in utero, which gives a leg up on early diagnosis and prevention. The giveaways are heart tumors on ECG and cortical tubers on fetal MRI.

Dr. Jozwiak thinks the prevention approach might also help in other early seizure disorders, such as Sturge-Weber syndrome.

The work was funded by the European Commission and Polish government. Dr. Jozwiak and Dr. Kotulska-Jozwiak didn’t have any disclosures.
 

[email protected]

SOURCES: Jozwiak S et al. AES 2019, Abstract 1.218; Kotulska-Jozwiak K et al. AES 2019, Abstract 2.121.

In addition to offering an overall survival benefit for patients with MGMT-methylated glioblastoma, the combination of lomustine and temozolomide did not impair health-related quality of life (HRQOL) compared with temozolomide alone, investigators report.

Among 129 patients with newly-diagnosed glioblastoma with methylation of the MGMT promoter, there were no significant differences in any items on the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 and the EORTC brain cancer module (BN20) between patients who received oral combined lomustine and temozolomide or temozolomide alone, reported Johannes Weller, MD, of University Hospital Bonn, Germany, and colleagues.

Although the combination was associated with slightly lower scores on the Mini-Mental State Exam (MMSE), the differences were not clinically significant, the investigators asserted.

“The absence of systematic and clinically relevant changes in HRQOL and neurocognitive function combined with the survival benefit of lomustine-temozolomide versus temozolomide alone suggests that a long-term net clinical benefit exists for patients with newly diagnosed glioblastoma with methylation of the MGMT promoter and supports the use of lomustine-temozolomide as a treatment option for these patients,” they wrote. The report is in The Lancet Oncology.

The investigators previously reported that median overall survival was improved from 31.4 months with temozolomide to 48.1 months with lomustine-temozolomide, translating into a hazard ratio (HR) for death with the combination of 0.60 (P = .0492).

In the current report, Dr. Weller and associates looked at the secondary endpoints of HRQOL as measured by the EORTC scales, and at neurocognitive function as assessed by the MMSE and a neurocognitive test battery (NOA-07) that include Trail Making Test A and B (TMT-A and B), working memory tests, and tests for word and semantic verbal fluency.

The modified intention-to-treat analysis included all patients who received at least one dose of study chemotherapy. The analysis included data on 63 patients randomly assigned to receive standard oral temozolomide, consisting of 75 mg/m² daily during radiotherapy plus six 4-week courses of temozolomide at doses ranging from 150 to 200 mg/m² on days 1-5, every 4 weeks; and 66 patients assigned to receive oral combined lomustine consisting of a 100 mg/m² dose on day 1, plus temozolomide 100 to 200 mg/m² on days 2-6 for six cycles of 6 weeks each.

After a median follow-up of 19.4 months for the HRQOL endpoint, there were no significant differences between the groups in decline from baselines in Karnofsky Performance Score, global health, physical functioning, cognitive functioning, social functioning, or communication deficit.

As noted before, however, there were small but significant differences between the groups favoring temozolomide on the MMSE, after a median follow-up for this measure of 15.3 months. The authors noted that the differences “were not significant when adjusted for multiple testing and were also not clinically relevant, because even over the time course of 4 years the differences between the groups would only add up to 1.76/30 points and clinically significant results would require a difference of more than 3/30 points.”

There were also no significant differences between the groups in any item of the neurocognitive test, they added.

The investigators acknowledged that the trial was limited by its relatively small size, and that after 3.5 years of follow-up about half of all the expected HRQOL forms were missing, which might lead to reporting bias.

“Overall, we conclude that the addition of lomustine to temozolomide in patients with newly diagnosed MGMT-methylated glioblastoma is associated with a clear long-term net clinical benefit and our data provide a good rationale for the trial regimen as a treatment option for these patients. Nevertheless, changes in HRQOL during the first year after beginning treatment needs further exploration in future studies,” Dr. Weller and colleagues wrote.

The German Federal Ministry of Education and Research funded the study. Dr. Weller reported having no conflict of interest. Several coauthors reported relationships with industry outside the submitted work.

SOURCE: Weller J et al. Lancet Oncol. Sept 2. doi: 10.1016/S1470-2045(19)30502-9.

In addition to offering an overall survival benefit for patients with MGMT-methylated glioblastoma, the combination of lomustine and temozolomide did not impair health-related quality of life (HRQOL) compared with temozolomide alone, investigators report.

Among 129 patients with newly-diagnosed glioblastoma with methylation of the MGMT promoter, there were no significant differences in any items on the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 and the EORTC brain cancer module (BN20) between patients who received oral combined lomustine and temozolomide or temozolomide alone, reported Johannes Weller, MD, of University Hospital Bonn, Germany, and colleagues.

Although the combination was associated with slightly lower scores on the Mini-Mental State Exam (MMSE), the differences were not clinically significant, the investigators asserted.

“The absence of systematic and clinically relevant changes in HRQOL and neurocognitive function combined with the survival benefit of lomustine-temozolomide versus temozolomide alone suggests that a long-term net clinical benefit exists for patients with newly diagnosed glioblastoma with methylation of the MGMT promoter and supports the use of lomustine-temozolomide as a treatment option for these patients,” they wrote. The report is in The Lancet Oncology.

The investigators previously reported that median overall survival was improved from 31.4 months with temozolomide to 48.1 months with lomustine-temozolomide, translating into a hazard ratio (HR) for death with the combination of 0.60 (P = .0492).

In the current report, Dr. Weller and associates looked at the secondary endpoints of HRQOL as measured by the EORTC scales, and at neurocognitive function as assessed by the MMSE and a neurocognitive test battery (NOA-07) that include Trail Making Test A and B (TMT-A and B), working memory tests, and tests for word and semantic verbal fluency.

The modified intention-to-treat analysis included all patients who received at least one dose of study chemotherapy. The analysis included data on 63 patients randomly assigned to receive standard oral temozolomide, consisting of 75 mg/m² daily during radiotherapy plus six 4-week courses of temozolomide at doses ranging from 150 to 200 mg/m² on days 1-5, every 4 weeks; and 66 patients assigned to receive oral combined lomustine consisting of a 100 mg/m² dose on day 1, plus temozolomide 100 to 200 mg/m² on days 2-6 for six cycles of 6 weeks each.

After a median follow-up of 19.4 months for the HRQOL endpoint, there were no significant differences between the groups in decline from baselines in Karnofsky Performance Score, global health, physical functioning, cognitive functioning, social functioning, or communication deficit.

As noted before, however, there were small but significant differences between the groups favoring temozolomide on the MMSE, after a median follow-up for this measure of 15.3 months. The authors noted that the differences “were not significant when adjusted for multiple testing and were also not clinically relevant, because even over the time course of 4 years the differences between the groups would only add up to 1.76/30 points and clinically significant results would require a difference of more than 3/30 points.”

There were also no significant differences between the groups in any item of the neurocognitive test, they added.

The investigators acknowledged that the trial was limited by its relatively small size, and that after 3.5 years of follow-up about half of all the expected HRQOL forms were missing, which might lead to reporting bias.

“Overall, we conclude that the addition of lomustine to temozolomide in patients with newly diagnosed MGMT-methylated glioblastoma is associated with a clear long-term net clinical benefit and our data provide a good rationale for the trial regimen as a treatment option for these patients. Nevertheless, changes in HRQOL during the first year after beginning treatment needs further exploration in future studies,” Dr. Weller and colleagues wrote.

The German Federal Ministry of Education and Research funded the study. Dr. Weller reported having no conflict of interest. Several coauthors reported relationships with industry outside the submitted work.

SOURCE: Weller J et al. Lancet Oncol. Sept 2. doi: 10.1016/S1470-2045(19)30502-9.

In addition to offering an overall survival benefit for patients with MGMT-methylated glioblastoma, the combination of lomustine and temozolomide did not impair health-related quality of life (HRQOL) compared with temozolomide alone, investigators report.

Among 129 patients with newly-diagnosed glioblastoma with methylation of the MGMT promoter, there were no significant differences in any items on the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 and the EORTC brain cancer module (BN20) between patients who received oral combined lomustine and temozolomide or temozolomide alone, reported Johannes Weller, MD, of University Hospital Bonn, Germany, and colleagues.

Although the combination was associated with slightly lower scores on the Mini-Mental State Exam (MMSE), the differences were not clinically significant, the investigators asserted.

“The absence of systematic and clinically relevant changes in HRQOL and neurocognitive function combined with the survival benefit of lomustine-temozolomide versus temozolomide alone suggests that a long-term net clinical benefit exists for patients with newly diagnosed glioblastoma with methylation of the MGMT promoter and supports the use of lomustine-temozolomide as a treatment option for these patients,” they wrote. The report is in The Lancet Oncology.

The investigators previously reported that median overall survival was improved from 31.4 months with temozolomide to 48.1 months with lomustine-temozolomide, translating into a hazard ratio (HR) for death with the combination of 0.60 (P = .0492).

In the current report, Dr. Weller and associates looked at the secondary endpoints of HRQOL as measured by the EORTC scales, and at neurocognitive function as assessed by the MMSE and a neurocognitive test battery (NOA-07) that include Trail Making Test A and B (TMT-A and B), working memory tests, and tests for word and semantic verbal fluency.

The modified intention-to-treat analysis included all patients who received at least one dose of study chemotherapy. The analysis included data on 63 patients randomly assigned to receive standard oral temozolomide, consisting of 75 mg/m² daily during radiotherapy plus six 4-week courses of temozolomide at doses ranging from 150 to 200 mg/m² on days 1-5, every 4 weeks; and 66 patients assigned to receive oral combined lomustine consisting of a 100 mg/m² dose on day 1, plus temozolomide 100 to 200 mg/m² on days 2-6 for six cycles of 6 weeks each.

After a median follow-up of 19.4 months for the HRQOL endpoint, there were no significant differences between the groups in decline from baselines in Karnofsky Performance Score, global health, physical functioning, cognitive functioning, social functioning, or communication deficit.

As noted before, however, there were small but significant differences between the groups favoring temozolomide on the MMSE, after a median follow-up for this measure of 15.3 months. The authors noted that the differences “were not significant when adjusted for multiple testing and were also not clinically relevant, because even over the time course of 4 years the differences between the groups would only add up to 1.76/30 points and clinically significant results would require a difference of more than 3/30 points.”

There were also no significant differences between the groups in any item of the neurocognitive test, they added.

The investigators acknowledged that the trial was limited by its relatively small size, and that after 3.5 years of follow-up about half of all the expected HRQOL forms were missing, which might lead to reporting bias.

“Overall, we conclude that the addition of lomustine to temozolomide in patients with newly diagnosed MGMT-methylated glioblastoma is associated with a clear long-term net clinical benefit and our data provide a good rationale for the trial regimen as a treatment option for these patients. Nevertheless, changes in HRQOL during the first year after beginning treatment needs further exploration in future studies,” Dr. Weller and colleagues wrote.

The German Federal Ministry of Education and Research funded the study. Dr. Weller reported having no conflict of interest. Several coauthors reported relationships with industry outside the submitted work.

SOURCE: Weller J et al. Lancet Oncol. Sept 2. doi: 10.1016/S1470-2045(19)30502-9.

BUSAN, SOUTH KOREA – Sodium-glucose transporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes seem to be as safe and effective in people aged 65 years and older as they are in younger individuals, new research suggests.

Findings from a real-world observational study of 50 older adults with type 2 diabetes were recently presented at the International Diabetes Federation congress by Carlos Trescoli-Serrano, MD, of Hospital Universitario de la Ribera, Valencia, Spain.

“The results are quite similar to those of younger people. … In a selected population they are safe. It doesn’t matter if patients are older or younger. You have to review the patients for complications,” Dr. Trescoli-Serrano said in an interview.

Asked to comment, session moderator Samuel Dagogo-Jack, MD, said: “We need more and more studies in older people for reassurance. The elderly have impaired kidneys, and these drugs depend on kidney filtration. It’s good to have data on elderly patients in the real world.”
 

Most had comorbidities

The 50 adults were a mean age of 67 years, and the oldest was 81 years. They had a mean diabetes duration of 12.5 years, and 40% were women. They had all been taking SGLT2 inhibitors for more than 3 years (mean 43.9 months) during 2015-2019.

At baseline, most (75%) were also taking metformin, 45% also took sulfonylureas, 37% dipeptidyl peptidase-4 (DPP-4) inhibitors, and 36% insulin.

Most (81%) also had hypertension, half (51%) had hypercholesterolemia, a third (33%) had obesity, and 32% had a previous cardiovascular event.

With SGLT2-inhibitor treatment, the average hemoglobin A_1c level dropped from 8.5% to 7.3% (P less than .01), body weight was reduced from 91.0 kg to 84.7 kg (P less than .01), systolic blood pressure from 134.5 mm Hg to 130.4 mm Hg (P = .02), and diastolic blood pressure from 76.2 mm Hg to 73.3 mm Hg (P = .04).

This effect on blood pressure “should be considered” because it means that “antihypertensive treatment might need to be reviewed,” Dr. Trescoli-Serrano commented.

There were no significant changes in estimated glomerular filtration rate (eGFR), microalbuminuria, lipid profile, hematocrit, or heart rate, although there were positive trends in both renal function and lipid profiles.

No patient had a fall, volume depletion symptoms, or diabetic ketoacidosis. However, 38% of patients were treated for urinary-genital infections, and 8% had to stop taking the SGLT2 inhibitor because of such infections.

That percentage seemed unusually high and was “an outlier, not the general experience,” commented Dr. Dagogo-Jack, chief of the Division of Endocrinology, Diabetes and Metabolism at the University of Tennessee Health Science Center, Memphis. He noted that infections with SGLT2 inhibitors are more often genital fungal than urinary tract infections, but the latter are more common in people with diabetes overall, and the study wasn’t randomized, so this might explain the finding.

New nonfatal cardiovascular events occurred in 22% of the patients, mainly cerebrovascular disease during the treatment period. Of those, 66% had had a previous cardiovascular event prior to starting on SGLT2 inhibitors.

Severe hypoglycemia was recorded in one patient, who was also taking insulin. Overall 10% died, mainly because of neoplastic causes.

“Long-term treatment with SGLT2 inhibitors are safe and effective when added to not-well-controlled elderly type 2 diabetes patients in a real-world experience,” Dr. Trescoli-Serrano concluded.

Dr. Dagogo-Jack is a consultant for Merck, Janssen, and Sanofi and owns stock in Dance Pharma and Jana Care.



A version of this story originally appeared on Medscape.com.

BUSAN, SOUTH KOREA – Sodium-glucose transporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes seem to be as safe and effective in people aged 65 years and older as they are in younger individuals, new research suggests.

Findings from a real-world observational study of 50 older adults with type 2 diabetes were recently presented at the International Diabetes Federation congress by Carlos Trescoli-Serrano, MD, of Hospital Universitario de la Ribera, Valencia, Spain.

“The results are quite similar to those of younger people. … In a selected population they are safe. It doesn’t matter if patients are older or younger. You have to review the patients for complications,” Dr. Trescoli-Serrano said in an interview.

Asked to comment, session moderator Samuel Dagogo-Jack, MD, said: “We need more and more studies in older people for reassurance. The elderly have impaired kidneys, and these drugs depend on kidney filtration. It’s good to have data on elderly patients in the real world.”
 

Most had comorbidities

The 50 adults were a mean age of 67 years, and the oldest was 81 years. They had a mean diabetes duration of 12.5 years, and 40% were women. They had all been taking SGLT2 inhibitors for more than 3 years (mean 43.9 months) during 2015-2019.

At baseline, most (75%) were also taking metformin, 45% also took sulfonylureas, 37% dipeptidyl peptidase-4 (DPP-4) inhibitors, and 36% insulin.

Most (81%) also had hypertension, half (51%) had hypercholesterolemia, a third (33%) had obesity, and 32% had a previous cardiovascular event.

With SGLT2-inhibitor treatment, the average hemoglobin A_1c level dropped from 8.5% to 7.3% (P less than .01), body weight was reduced from 91.0 kg to 84.7 kg (P less than .01), systolic blood pressure from 134.5 mm Hg to 130.4 mm Hg (P = .02), and diastolic blood pressure from 76.2 mm Hg to 73.3 mm Hg (P = .04).

This effect on blood pressure “should be considered” because it means that “antihypertensive treatment might need to be reviewed,” Dr. Trescoli-Serrano commented.

There were no significant changes in estimated glomerular filtration rate (eGFR), microalbuminuria, lipid profile, hematocrit, or heart rate, although there were positive trends in both renal function and lipid profiles.

No patient had a fall, volume depletion symptoms, or diabetic ketoacidosis. However, 38% of patients were treated for urinary-genital infections, and 8% had to stop taking the SGLT2 inhibitor because of such infections.

That percentage seemed unusually high and was “an outlier, not the general experience,” commented Dr. Dagogo-Jack, chief of the Division of Endocrinology, Diabetes and Metabolism at the University of Tennessee Health Science Center, Memphis. He noted that infections with SGLT2 inhibitors are more often genital fungal than urinary tract infections, but the latter are more common in people with diabetes overall, and the study wasn’t randomized, so this might explain the finding.

New nonfatal cardiovascular events occurred in 22% of the patients, mainly cerebrovascular disease during the treatment period. Of those, 66% had had a previous cardiovascular event prior to starting on SGLT2 inhibitors.

Severe hypoglycemia was recorded in one patient, who was also taking insulin. Overall 10% died, mainly because of neoplastic causes.

“Long-term treatment with SGLT2 inhibitors are safe and effective when added to not-well-controlled elderly type 2 diabetes patients in a real-world experience,” Dr. Trescoli-Serrano concluded.

Dr. Dagogo-Jack is a consultant for Merck, Janssen, and Sanofi and owns stock in Dance Pharma and Jana Care.



A version of this story originally appeared on Medscape.com.

BUSAN, SOUTH KOREA – Sodium-glucose transporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes seem to be as safe and effective in people aged 65 years and older as they are in younger individuals, new research suggests.

Findings from a real-world observational study of 50 older adults with type 2 diabetes were recently presented at the International Diabetes Federation congress by Carlos Trescoli-Serrano, MD, of Hospital Universitario de la Ribera, Valencia, Spain.

“The results are quite similar to those of younger people. … In a selected population they are safe. It doesn’t matter if patients are older or younger. You have to review the patients for complications,” Dr. Trescoli-Serrano said in an interview.

Asked to comment, session moderator Samuel Dagogo-Jack, MD, said: “We need more and more studies in older people for reassurance. The elderly have impaired kidneys, and these drugs depend on kidney filtration. It’s good to have data on elderly patients in the real world.”
 

Most had comorbidities

The 50 adults were a mean age of 67 years, and the oldest was 81 years. They had a mean diabetes duration of 12.5 years, and 40% were women. They had all been taking SGLT2 inhibitors for more than 3 years (mean 43.9 months) during 2015-2019.

At baseline, most (75%) were also taking metformin, 45% also took sulfonylureas, 37% dipeptidyl peptidase-4 (DPP-4) inhibitors, and 36% insulin.

Most (81%) also had hypertension, half (51%) had hypercholesterolemia, a third (33%) had obesity, and 32% had a previous cardiovascular event.

With SGLT2-inhibitor treatment, the average hemoglobin A_1c level dropped from 8.5% to 7.3% (P less than .01), body weight was reduced from 91.0 kg to 84.7 kg (P less than .01), systolic blood pressure from 134.5 mm Hg to 130.4 mm Hg (P = .02), and diastolic blood pressure from 76.2 mm Hg to 73.3 mm Hg (P = .04).

This effect on blood pressure “should be considered” because it means that “antihypertensive treatment might need to be reviewed,” Dr. Trescoli-Serrano commented.

There were no significant changes in estimated glomerular filtration rate (eGFR), microalbuminuria, lipid profile, hematocrit, or heart rate, although there were positive trends in both renal function and lipid profiles.

No patient had a fall, volume depletion symptoms, or diabetic ketoacidosis. However, 38% of patients were treated for urinary-genital infections, and 8% had to stop taking the SGLT2 inhibitor because of such infections.

That percentage seemed unusually high and was “an outlier, not the general experience,” commented Dr. Dagogo-Jack, chief of the Division of Endocrinology, Diabetes and Metabolism at the University of Tennessee Health Science Center, Memphis. He noted that infections with SGLT2 inhibitors are more often genital fungal than urinary tract infections, but the latter are more common in people with diabetes overall, and the study wasn’t randomized, so this might explain the finding.

New nonfatal cardiovascular events occurred in 22% of the patients, mainly cerebrovascular disease during the treatment period. Of those, 66% had had a previous cardiovascular event prior to starting on SGLT2 inhibitors.

Severe hypoglycemia was recorded in one patient, who was also taking insulin. Overall 10% died, mainly because of neoplastic causes.

“Long-term treatment with SGLT2 inhibitors are safe and effective when added to not-well-controlled elderly type 2 diabetes patients in a real-world experience,” Dr. Trescoli-Serrano concluded.

Dr. Dagogo-Jack is a consultant for Merck, Janssen, and Sanofi and owns stock in Dance Pharma and Jana Care.



A version of this story originally appeared on Medscape.com.

A newly approved triple-combination modulator to treat cystic fibrosis (CF) has raised expectations of a treatment turning point among patients and specialists. If the early results are sustained, elexacaftor/ivacaftor/tezacaftor (Trikafta) could prove to be the rare case of a much-touted new medicine that meets high expectations.

Courtesy Susan Millard, MD

“CF even in infants causes inflammation, so we know that lung damage can start early and progress,” said Susan Millard, MD, FCCP, of Helen DeVos Children’s Hospital in Grand Rapids, Mich., and the local clinical research director for the pediatric pulmonary and sleep medicine section. “This oral drug therapy is actually treating the underlying problem, as opposed to many of the therapies we have that take hours to nebulize and only work locally in the airways.”

Dr. Millard is the recent past pediatric editor for Chest Physician and has been a local principal investigator at Helen DeVos Children’s Hospital for many Vertex-sponsored clinical studies.

The pivotal studies

The Food and Drug Administration approval of Trikafta rested on two pivotal phase 3, placebo-controlled studies, one in patients with two copies of the most common CF mutations, F508del, and the second in patients with one copy of F508del and a second mutation that was called a “minimal-function” mutation. The findings have ignited the hopes of many people with CF and their physicians. The drug was approved in October 2019 for patients aged 12 years and older who have at least one F508del mutation of the cystic fibrosis transmembrane conductance regulator gene. About 90% of patients in the United States have at least one copy of F508del. In the study looking at patients with one copy of F508del, the mean predicted forced expiratory volume in 1 second increased 13.8% in patients taking the drug versus placebo (N Engl J Med. 2019 Oct 31. doi: 10.1056/NEJMoa1908639). The number of pulmonary exacerbations decreased by 63% in the Trikafta group, compared with placebo. Pulmonary exacerbations were described as a change in specific symptoms that required treatment with a new oral, intravenous, or inhaled antibiotic. Serious adverse drug reactions that occurred more frequently in patients receiving Trikafta, compared with placebo, were rash and influenza events.

In the study that included patients with two copies of F508del, on average, the lung function increased 10% versus patients on ivacaftor/tezacaftor at 4 weeks. In addition, there was a 45.1 mmol/L on average decrease in the sweat chloride level in the Trikafta group, compared with ivacaftor/tezacaftor.
 

A hopeful start

Robert Giusti, MD, a pediatric pulmonologist at New York University Langone Health, is also hopeful. “This could be the kind of treatment that will make a revolution in terms of [cystic fibrosis] care if it can be started very early in life shortly after diagnosis. We anticipate that patients will be disease free for a longer period of time.”

The Cystic Fibrosis Foundation’s (CFF) “venture philanthropy” initiative played an important role in the development of the drug by Vertex Pharmaceuticals. The CFF has invested many millions of dollars in research by drug companies since the 1980s and was an early backer of Vertex. According to a statement on the CFF website, the Foundation sold its royalty rights for treatments developed by Vertex for $3.3 billion in 2014. The drug has a list price of about $311,000 a year. Payment issues may arise in the future, but for now, Vertex has stated that insurers and some Medicaid programs have begun paying claims for Trikafta

Specialists who treat CF now are watching to see how well patients tolerate this highly anticipated drug – and how well it meets expectations. The Therapeutic Development Network, the clinical research division of the CFF, is enrolling patients taking Trikafta in an observational study to follow for long-term follow-up.
 

Meeting expectations

“[Long-term efficacy is] something that we’re always concerned about. When the drug comes to market, is it going to be as effective as we thought it might be?” said Ryan Thomas, MD, director of the Cystic Fibrosis Center at Michigan State University, East Lansing. The MSU Cystic Fibrosis Center receives funding from the Cystic Fibrosis Foundation.

A different disease

Trikafta is the latest in a series of improvements of CF treatment in recent decades, recalled Dr. Giusti, who has been in this field for about 3 decades. “It used to be that I attended many funerals for children with CF. Now with patients living longer and healthier lives I am invited to attend their weddings and even their children’s baptisms and bris ceremonies. It is a very different disease than it used to be.”

The promise of Trikafta leaves behind the minority of patients for whom the drug won’t work. This is for the 10% of patients that have rare mutations. That can lead to difficult conversations with parents about why this new option is not a choice for their child, Dr. Millard said. “It just crushes you, but the Cystic Fibrosis Foundation is committing a lot of new research in that direction. Their mantra is ‘until it is done.’ ”
 

Realistic expectations

William (Randy) Hunt, MD, FAAP, FACP, assistant professor of medicine in the Division of Pulmonary, Allergy, Critical Care and Sleep, Emory University School of Medicine, Atlanta, agrees that Trikafta is an exciting development in CF treatment. He noted,  “Starting this medication early in life may very well significantly attenuate the disease, but it is not a cure. For individuals who already have significant disease, we may not see the same level of improvements in lung function as what we saw in the studies. The studies generally excluded individuals with ppFEV1 < 40%.  Nevertheless, I remain optimistic and have been prescribing it to nearly everyone that qualifies after a discussion.” 

Dr. Hunt added, “Patients are asking if they can stop their current chronic CF therapies once they start Trikafta. The answer is “no, at least not right now.” While all the relatively short-term data around Trikafta are very promising, we do not yet know how sustained the long-term benefits will be.  Still, safely removing therapeutic burden from our patient population is a real interest. There are plans underway by the CFF and other institutions to systematically research whether discontinuing chronic CF therapies is safe in the setting of Trikafta.”

He concluded that 10% of individuals with CF mutations still do not respond to the modulators currently available. “We will not leave that population behind, but treating these remaining mutations is going to take continued efforts and likely modulators that are therapeutically differently from the mechanism of actions of those that are currently available,” he said.
 

Therese Borden contributed to this article.

1/2/2020 - This story was updated.

A newly approved triple-combination modulator to treat cystic fibrosis (CF) has raised expectations of a treatment turning point among patients and specialists. If the early results are sustained, elexacaftor/ivacaftor/tezacaftor (Trikafta) could prove to be the rare case of a much-touted new medicine that meets high expectations.

Courtesy Susan Millard, MD

“CF even in infants causes inflammation, so we know that lung damage can start early and progress,” said Susan Millard, MD, FCCP, of Helen DeVos Children’s Hospital in Grand Rapids, Mich., and the local clinical research director for the pediatric pulmonary and sleep medicine section. “This oral drug therapy is actually treating the underlying problem, as opposed to many of the therapies we have that take hours to nebulize and only work locally in the airways.”

Dr. Millard is the recent past pediatric editor for Chest Physician and has been a local principal investigator at Helen DeVos Children’s Hospital for many Vertex-sponsored clinical studies.

The pivotal studies

The Food and Drug Administration approval of Trikafta rested on two pivotal phase 3, placebo-controlled studies, one in patients with two copies of the most common CF mutations, F508del, and the second in patients with one copy of F508del and a second mutation that was called a “minimal-function” mutation. The findings have ignited the hopes of many people with CF and their physicians. The drug was approved in October 2019 for patients aged 12 years and older who have at least one F508del mutation of the cystic fibrosis transmembrane conductance regulator gene. About 90% of patients in the United States have at least one copy of F508del. In the study looking at patients with one copy of F508del, the mean predicted forced expiratory volume in 1 second increased 13.8% in patients taking the drug versus placebo (N Engl J Med. 2019 Oct 31. doi: 10.1056/NEJMoa1908639). The number of pulmonary exacerbations decreased by 63% in the Trikafta group, compared with placebo. Pulmonary exacerbations were described as a change in specific symptoms that required treatment with a new oral, intravenous, or inhaled antibiotic. Serious adverse drug reactions that occurred more frequently in patients receiving Trikafta, compared with placebo, were rash and influenza events.

In the study that included patients with two copies of F508del, on average, the lung function increased 10% versus patients on ivacaftor/tezacaftor at 4 weeks. In addition, there was a 45.1 mmol/L on average decrease in the sweat chloride level in the Trikafta group, compared with ivacaftor/tezacaftor.
 

A hopeful start

Robert Giusti, MD, a pediatric pulmonologist at New York University Langone Health, is also hopeful. “This could be the kind of treatment that will make a revolution in terms of [cystic fibrosis] care if it can be started very early in life shortly after diagnosis. We anticipate that patients will be disease free for a longer period of time.”

The Cystic Fibrosis Foundation’s (CFF) “venture philanthropy” initiative played an important role in the development of the drug by Vertex Pharmaceuticals. The CFF has invested many millions of dollars in research by drug companies since the 1980s and was an early backer of Vertex. According to a statement on the CFF website, the Foundation sold its royalty rights for treatments developed by Vertex for $3.3 billion in 2014. The drug has a list price of about $311,000 a year. Payment issues may arise in the future, but for now, Vertex has stated that insurers and some Medicaid programs have begun paying claims for Trikafta

Specialists who treat CF now are watching to see how well patients tolerate this highly anticipated drug – and how well it meets expectations. The Therapeutic Development Network, the clinical research division of the CFF, is enrolling patients taking Trikafta in an observational study to follow for long-term follow-up.
 

Meeting expectations

“[Long-term efficacy is] something that we’re always concerned about. When the drug comes to market, is it going to be as effective as we thought it might be?” said Ryan Thomas, MD, director of the Cystic Fibrosis Center at Michigan State University, East Lansing. The MSU Cystic Fibrosis Center receives funding from the Cystic Fibrosis Foundation.

A different disease

Trikafta is the latest in a series of improvements of CF treatment in recent decades, recalled Dr. Giusti, who has been in this field for about 3 decades. “It used to be that I attended many funerals for children with CF. Now with patients living longer and healthier lives I am invited to attend their weddings and even their children’s baptisms and bris ceremonies. It is a very different disease than it used to be.”

The promise of Trikafta leaves behind the minority of patients for whom the drug won’t work. This is for the 10% of patients that have rare mutations. That can lead to difficult conversations with parents about why this new option is not a choice for their child, Dr. Millard said. “It just crushes you, but the Cystic Fibrosis Foundation is committing a lot of new research in that direction. Their mantra is ‘until it is done.’ ”
 

Realistic expectations

William (Randy) Hunt, MD, FAAP, FACP, assistant professor of medicine in the Division of Pulmonary, Allergy, Critical Care and Sleep, Emory University School of Medicine, Atlanta, agrees that Trikafta is an exciting development in CF treatment. He noted,  “Starting this medication early in life may very well significantly attenuate the disease, but it is not a cure. For individuals who already have significant disease, we may not see the same level of improvements in lung function as what we saw in the studies. The studies generally excluded individuals with ppFEV1 < 40%.  Nevertheless, I remain optimistic and have been prescribing it to nearly everyone that qualifies after a discussion.” 

Dr. Hunt added, “Patients are asking if they can stop their current chronic CF therapies once they start Trikafta. The answer is “no, at least not right now.” While all the relatively short-term data around Trikafta are very promising, we do not yet know how sustained the long-term benefits will be.  Still, safely removing therapeutic burden from our patient population is a real interest. There are plans underway by the CFF and other institutions to systematically research whether discontinuing chronic CF therapies is safe in the setting of Trikafta.”

He concluded that 10% of individuals with CF mutations still do not respond to the modulators currently available. “We will not leave that population behind, but treating these remaining mutations is going to take continued efforts and likely modulators that are therapeutically differently from the mechanism of actions of those that are currently available,” he said.
 

Therese Borden contributed to this article.

1/2/2020 - This story was updated.

A newly approved triple-combination modulator to treat cystic fibrosis (CF) has raised expectations of a treatment turning point among patients and specialists. If the early results are sustained, elexacaftor/ivacaftor/tezacaftor (Trikafta) could prove to be the rare case of a much-touted new medicine that meets high expectations.

Courtesy Susan Millard, MD

“CF even in infants causes inflammation, so we know that lung damage can start early and progress,” said Susan Millard, MD, FCCP, of Helen DeVos Children’s Hospital in Grand Rapids, Mich., and the local clinical research director for the pediatric pulmonary and sleep medicine section. “This oral drug therapy is actually treating the underlying problem, as opposed to many of the therapies we have that take hours to nebulize and only work locally in the airways.”

Dr. Millard is the recent past pediatric editor for Chest Physician and has been a local principal investigator at Helen DeVos Children’s Hospital for many Vertex-sponsored clinical studies.

The pivotal studies

The Food and Drug Administration approval of Trikafta rested on two pivotal phase 3, placebo-controlled studies, one in patients with two copies of the most common CF mutations, F508del, and the second in patients with one copy of F508del and a second mutation that was called a “minimal-function” mutation. The findings have ignited the hopes of many people with CF and their physicians. The drug was approved in October 2019 for patients aged 12 years and older who have at least one F508del mutation of the cystic fibrosis transmembrane conductance regulator gene. About 90% of patients in the United States have at least one copy of F508del. In the study looking at patients with one copy of F508del, the mean predicted forced expiratory volume in 1 second increased 13.8% in patients taking the drug versus placebo (N Engl J Med. 2019 Oct 31. doi: 10.1056/NEJMoa1908639). The number of pulmonary exacerbations decreased by 63% in the Trikafta group, compared with placebo. Pulmonary exacerbations were described as a change in specific symptoms that required treatment with a new oral, intravenous, or inhaled antibiotic. Serious adverse drug reactions that occurred more frequently in patients receiving Trikafta, compared with placebo, were rash and influenza events.

In the study that included patients with two copies of F508del, on average, the lung function increased 10% versus patients on ivacaftor/tezacaftor at 4 weeks. In addition, there was a 45.1 mmol/L on average decrease in the sweat chloride level in the Trikafta group, compared with ivacaftor/tezacaftor.
 

A hopeful start

Robert Giusti, MD, a pediatric pulmonologist at New York University Langone Health, is also hopeful. “This could be the kind of treatment that will make a revolution in terms of [cystic fibrosis] care if it can be started very early in life shortly after diagnosis. We anticipate that patients will be disease free for a longer period of time.”

The Cystic Fibrosis Foundation’s (CFF) “venture philanthropy” initiative played an important role in the development of the drug by Vertex Pharmaceuticals. The CFF has invested many millions of dollars in research by drug companies since the 1980s and was an early backer of Vertex. According to a statement on the CFF website, the Foundation sold its royalty rights for treatments developed by Vertex for $3.3 billion in 2014. The drug has a list price of about $311,000 a year. Payment issues may arise in the future, but for now, Vertex has stated that insurers and some Medicaid programs have begun paying claims for Trikafta

Specialists who treat CF now are watching to see how well patients tolerate this highly anticipated drug – and how well it meets expectations. The Therapeutic Development Network, the clinical research division of the CFF, is enrolling patients taking Trikafta in an observational study to follow for long-term follow-up.
 

Meeting expectations

“[Long-term efficacy is] something that we’re always concerned about. When the drug comes to market, is it going to be as effective as we thought it might be?” said Ryan Thomas, MD, director of the Cystic Fibrosis Center at Michigan State University, East Lansing. The MSU Cystic Fibrosis Center receives funding from the Cystic Fibrosis Foundation.

A different disease

Trikafta is the latest in a series of improvements of CF treatment in recent decades, recalled Dr. Giusti, who has been in this field for about 3 decades. “It used to be that I attended many funerals for children with CF. Now with patients living longer and healthier lives I am invited to attend their weddings and even their children’s baptisms and bris ceremonies. It is a very different disease than it used to be.”

The promise of Trikafta leaves behind the minority of patients for whom the drug won’t work. This is for the 10% of patients that have rare mutations. That can lead to difficult conversations with parents about why this new option is not a choice for their child, Dr. Millard said. “It just crushes you, but the Cystic Fibrosis Foundation is committing a lot of new research in that direction. Their mantra is ‘until it is done.’ ”
 

Realistic expectations

William (Randy) Hunt, MD, FAAP, FACP, assistant professor of medicine in the Division of Pulmonary, Allergy, Critical Care and Sleep, Emory University School of Medicine, Atlanta, agrees that Trikafta is an exciting development in CF treatment. He noted,  “Starting this medication early in life may very well significantly attenuate the disease, but it is not a cure. For individuals who already have significant disease, we may not see the same level of improvements in lung function as what we saw in the studies. The studies generally excluded individuals with ppFEV1 < 40%.  Nevertheless, I remain optimistic and have been prescribing it to nearly everyone that qualifies after a discussion.” 

Dr. Hunt added, “Patients are asking if they can stop their current chronic CF therapies once they start Trikafta. The answer is “no, at least not right now.” While all the relatively short-term data around Trikafta are very promising, we do not yet know how sustained the long-term benefits will be.  Still, safely removing therapeutic burden from our patient population is a real interest. There are plans underway by the CFF and other institutions to systematically research whether discontinuing chronic CF therapies is safe in the setting of Trikafta.”

He concluded that 10% of individuals with CF mutations still do not respond to the modulators currently available. “We will not leave that population behind, but treating these remaining mutations is going to take continued efforts and likely modulators that are therapeutically differently from the mechanism of actions of those that are currently available,” he said.
 

Therese Borden contributed to this article.

1/2/2020 - This story was updated.

The Food and Drug Administration has approved two applications for first generic versions of apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) tablets to reduce the risk for stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

The FDA gave the go-ahead to market generic versions of apixaban to Micro Labs Limited and Mylan Pharmaceuticals.

“Today’s approvals of the first generics of apixaban are an example of how the FDA’s generic drug program improves access to lower-cost, safe, and high-quality medicines,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a statement today. “These approvals mark the first generic approvals of a direct oral anticoagulant.”

It is estimated that between 2.7 and 6.1 million people in the United States have atrial fibrillation. Many of these individuals use anticoagulants or anticlotting drugs to reduce that risk. Direct oral anticoagulants, however, do not require repeated blood testing.

Apixaban was approved by the FDA in December 2012 for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Additional indications in the United States are to treat and prevent the recurrence of deep vein thrombosis (DVT) and pulmonary embolism (PE) and as DVT/PE prophylaxis in adults who have undergone hip or knee replacement surgery.

The FDA reminds providers that, as with brand name apixaban, generic versions must be dispensed with a medication guide that provides important instructions on the drug’s uses and risks. Healthcare professionals should counsel patients on signs and symptoms of possible bleeding.

As with other FDA-approved anticlotting drugs, bleeding, including life-threatening and fatal bleeding, is the most serious risk with apixaban.

Full prescribing information for the drug also warns about the increased risk for stroke in patients who discontinue use of the drug without taking some other form of anticoagulation. Epidural or spinal hematoma, which may cause long-term or permanent paralysis, may occur in patients treated with apixaban who are undergoing spinal epidural anesthesia or spinal puncture.

This story first appeared on Medscape.com.

The Food and Drug Administration has approved two applications for first generic versions of apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) tablets to reduce the risk for stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

The FDA gave the go-ahead to market generic versions of apixaban to Micro Labs Limited and Mylan Pharmaceuticals.

“Today’s approvals of the first generics of apixaban are an example of how the FDA’s generic drug program improves access to lower-cost, safe, and high-quality medicines,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a statement today. “These approvals mark the first generic approvals of a direct oral anticoagulant.”

It is estimated that between 2.7 and 6.1 million people in the United States have atrial fibrillation. Many of these individuals use anticoagulants or anticlotting drugs to reduce that risk. Direct oral anticoagulants, however, do not require repeated blood testing.

Apixaban was approved by the FDA in December 2012 for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Additional indications in the United States are to treat and prevent the recurrence of deep vein thrombosis (DVT) and pulmonary embolism (PE) and as DVT/PE prophylaxis in adults who have undergone hip or knee replacement surgery.

The FDA reminds providers that, as with brand name apixaban, generic versions must be dispensed with a medication guide that provides important instructions on the drug’s uses and risks. Healthcare professionals should counsel patients on signs and symptoms of possible bleeding.

As with other FDA-approved anticlotting drugs, bleeding, including life-threatening and fatal bleeding, is the most serious risk with apixaban.

Full prescribing information for the drug also warns about the increased risk for stroke in patients who discontinue use of the drug without taking some other form of anticoagulation. Epidural or spinal hematoma, which may cause long-term or permanent paralysis, may occur in patients treated with apixaban who are undergoing spinal epidural anesthesia or spinal puncture.

This story first appeared on Medscape.com.

The Food and Drug Administration has approved two applications for first generic versions of apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) tablets to reduce the risk for stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

The FDA gave the go-ahead to market generic versions of apixaban to Micro Labs Limited and Mylan Pharmaceuticals.

“Today’s approvals of the first generics of apixaban are an example of how the FDA’s generic drug program improves access to lower-cost, safe, and high-quality medicines,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a statement today. “These approvals mark the first generic approvals of a direct oral anticoagulant.”

It is estimated that between 2.7 and 6.1 million people in the United States have atrial fibrillation. Many of these individuals use anticoagulants or anticlotting drugs to reduce that risk. Direct oral anticoagulants, however, do not require repeated blood testing.

Apixaban was approved by the FDA in December 2012 for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Additional indications in the United States are to treat and prevent the recurrence of deep vein thrombosis (DVT) and pulmonary embolism (PE) and as DVT/PE prophylaxis in adults who have undergone hip or knee replacement surgery.

The FDA reminds providers that, as with brand name apixaban, generic versions must be dispensed with a medication guide that provides important instructions on the drug’s uses and risks. Healthcare professionals should counsel patients on signs and symptoms of possible bleeding.

As with other FDA-approved anticlotting drugs, bleeding, including life-threatening and fatal bleeding, is the most serious risk with apixaban.

Full prescribing information for the drug also warns about the increased risk for stroke in patients who discontinue use of the drug without taking some other form of anticoagulation. Epidural or spinal hematoma, which may cause long-term or permanent paralysis, may occur in patients treated with apixaban who are undergoing spinal epidural anesthesia or spinal puncture.

This story first appeared on Medscape.com.

The Food and Drug Administration has approved ubrogepant (Ubrelvy, Allergan) for the acute treatment of migraine with or without aura in adults.

Olivier Le Moal/Getty Images

Ubrogepant is the first drug in the class of oral calcitonin gene–related peptide receptor antagonists approved for the acute treatment of migraine. It is approved in two dose strengths (50 mg and 100 mg).

The drug is not indicated, however, for the preventive treatment of migraine.

“Migraine is an often disabling condition that affects an estimated 37 million people in the U.S.,” Billy Dunn, MD, acting director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research, said in an FDA news release.

Ubrogepant represents “an important new option for the acute treatment of migraine in adults, as it is the first drug in its class approved for this indication. The FDA is pleased to approve a novel treatment for patients suffering from migraine and will continue to work with stakeholders to promote the development of new safe and effective migraine therapies,” added Dr. Dunn.

The safety and efficacy of ubrogepant for the acute treatment of migraine was demonstrated in two randomized, double-blind, placebo-controlled trials (ACHIEVE I and ACHIEVE II). In total, 1,439 adults with a history of migraine, with and without aura, received ubrogepant to treat an ongoing migraine.

“Both 50-mg and 100-mg dose strengths demonstrated significantly greater rates of pain freedom and freedom from the most bothersome migraine-associated symptom at 2 hours, compared with placebo,” Allergan said in a news release announcing approval.

The most common side effects reported by patients in the clinical trials were nausea, tiredness, and dry mouth. Ubrogepant is contraindicated for coadministration with strong CYP3A4 inhibitors.

The company expects to have ubrogepant available in the first quarter of 2020.

A version of this story originally appeared on Medscape.com.

The Food and Drug Administration has approved ubrogepant (Ubrelvy, Allergan) for the acute treatment of migraine with or without aura in adults.

Olivier Le Moal/Getty Images

Ubrogepant is the first drug in the class of oral calcitonin gene–related peptide receptor antagonists approved for the acute treatment of migraine. It is approved in two dose strengths (50 mg and 100 mg).

The drug is not indicated, however, for the preventive treatment of migraine.

“Migraine is an often disabling condition that affects an estimated 37 million people in the U.S.,” Billy Dunn, MD, acting director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research, said in an FDA news release.

Ubrogepant represents “an important new option for the acute treatment of migraine in adults, as it is the first drug in its class approved for this indication. The FDA is pleased to approve a novel treatment for patients suffering from migraine and will continue to work with stakeholders to promote the development of new safe and effective migraine therapies,” added Dr. Dunn.

The safety and efficacy of ubrogepant for the acute treatment of migraine was demonstrated in two randomized, double-blind, placebo-controlled trials (ACHIEVE I and ACHIEVE II). In total, 1,439 adults with a history of migraine, with and without aura, received ubrogepant to treat an ongoing migraine.

“Both 50-mg and 100-mg dose strengths demonstrated significantly greater rates of pain freedom and freedom from the most bothersome migraine-associated symptom at 2 hours, compared with placebo,” Allergan said in a news release announcing approval.

The most common side effects reported by patients in the clinical trials were nausea, tiredness, and dry mouth. Ubrogepant is contraindicated for coadministration with strong CYP3A4 inhibitors.

The company expects to have ubrogepant available in the first quarter of 2020.

A version of this story originally appeared on Medscape.com.

The Food and Drug Administration has approved ubrogepant (Ubrelvy, Allergan) for the acute treatment of migraine with or without aura in adults.

Olivier Le Moal/Getty Images

Ubrogepant is the first drug in the class of oral calcitonin gene–related peptide receptor antagonists approved for the acute treatment of migraine. It is approved in two dose strengths (50 mg and 100 mg).

The drug is not indicated, however, for the preventive treatment of migraine.

“Migraine is an often disabling condition that affects an estimated 37 million people in the U.S.,” Billy Dunn, MD, acting director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research, said in an FDA news release.

Ubrogepant represents “an important new option for the acute treatment of migraine in adults, as it is the first drug in its class approved for this indication. The FDA is pleased to approve a novel treatment for patients suffering from migraine and will continue to work with stakeholders to promote the development of new safe and effective migraine therapies,” added Dr. Dunn.

The safety and efficacy of ubrogepant for the acute treatment of migraine was demonstrated in two randomized, double-blind, placebo-controlled trials (ACHIEVE I and ACHIEVE II). In total, 1,439 adults with a history of migraine, with and without aura, received ubrogepant to treat an ongoing migraine.

“Both 50-mg and 100-mg dose strengths demonstrated significantly greater rates of pain freedom and freedom from the most bothersome migraine-associated symptom at 2 hours, compared with placebo,” Allergan said in a news release announcing approval.

The most common side effects reported by patients in the clinical trials were nausea, tiredness, and dry mouth. Ubrogepant is contraindicated for coadministration with strong CYP3A4 inhibitors.

The company expects to have ubrogepant available in the first quarter of 2020.

A version of this story originally appeared on Medscape.com.

WASHINGTON – Insulin is the preferred agent for type 2 diabetes in pregnant women, yet about a third of pregnancies still have an adverse outcome, according Kim Boggess, MD, who spoke at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

“We are not where we need to be,” said Dr. Boggess, who is leading a trial that brings metformin, the first-line agent for type 2 diabetes outside of pregnancy, back into the picture for pregnant women – as an add-on to insulin.

It is an interesting twist, because pregnant women taking metformin for preexisting type 2 or gestational diabetes have been shown in some studies to require supplemental insulin, more than occasionally, to achieve target glycemic control.

This was the case in a small, randomized, controlled trial at Dr. Boggess’ institution, the University of North Carolina at Chapel Hill, in which 43% of pregnant women with type 2 diabetes who were assigned to metformin required supplemental insulin (Am J Perinatol. 2013;30[6]:483-90). The study also found, however, that women treated with metformin had significantly fewer episodes of hypoglycemia, compared with women using insulin (0% vs. 36%, respectively) and fewer reports of glucose values less than 60 mg/dL (7.1% vs. 50%).

“I don’t consider this [need for supplemental insulin] ‘metformin failure,’ because studies that use metformin as monotherapy and that [show some patients] ultimately requiring insulin support ... also show that these women need less insulin,” she said. “What’s the risk of insulin alone? Hypoglycemia. So using less insulin could be a good thing.”

Other research suggests there may be less maternal weight gain, less neonatal hypoglycemia, fewer neonatal complications, and improved maternal glycemic control in patients treated with metformin, alone or with add-on insulin, than with insulin alone. “We’re starting to get a sense in the literature that, at least in the [pregnant] population with type 2 diabetes, there may be a role for metformin,” said Dr. Boggess, professor and program director for maternal-fetal medicine at the university.

* This article was updated 1/2/2020.

WASHINGTON – Insulin is the preferred agent for type 2 diabetes in pregnant women, yet about a third of pregnancies still have an adverse outcome, according Kim Boggess, MD, who spoke at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

“We are not where we need to be,” said Dr. Boggess, who is leading a trial that brings metformin, the first-line agent for type 2 diabetes outside of pregnancy, back into the picture for pregnant women – as an add-on to insulin.

It is an interesting twist, because pregnant women taking metformin for preexisting type 2 or gestational diabetes have been shown in some studies to require supplemental insulin, more than occasionally, to achieve target glycemic control.

This was the case in a small, randomized, controlled trial at Dr. Boggess’ institution, the University of North Carolina at Chapel Hill, in which 43% of pregnant women with type 2 diabetes who were assigned to metformin required supplemental insulin (Am J Perinatol. 2013;30[6]:483-90). The study also found, however, that women treated with metformin had significantly fewer episodes of hypoglycemia, compared with women using insulin (0% vs. 36%, respectively) and fewer reports of glucose values less than 60 mg/dL (7.1% vs. 50%).

“I don’t consider this [need for supplemental insulin] ‘metformin failure,’ because studies that use metformin as monotherapy and that [show some patients] ultimately requiring insulin support ... also show that these women need less insulin,” she said. “What’s the risk of insulin alone? Hypoglycemia. So using less insulin could be a good thing.”

Other research suggests there may be less maternal weight gain, less neonatal hypoglycemia, fewer neonatal complications, and improved maternal glycemic control in patients treated with metformin, alone or with add-on insulin, than with insulin alone. “We’re starting to get a sense in the literature that, at least in the [pregnant] population with type 2 diabetes, there may be a role for metformin,” said Dr. Boggess, professor and program director for maternal-fetal medicine at the university.

* This article was updated 1/2/2020.

WASHINGTON – Insulin is the preferred agent for type 2 diabetes in pregnant women, yet about a third of pregnancies still have an adverse outcome, according Kim Boggess, MD, who spoke at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

“We are not where we need to be,” said Dr. Boggess, who is leading a trial that brings metformin, the first-line agent for type 2 diabetes outside of pregnancy, back into the picture for pregnant women – as an add-on to insulin.

It is an interesting twist, because pregnant women taking metformin for preexisting type 2 or gestational diabetes have been shown in some studies to require supplemental insulin, more than occasionally, to achieve target glycemic control.

This was the case in a small, randomized, controlled trial at Dr. Boggess’ institution, the University of North Carolina at Chapel Hill, in which 43% of pregnant women with type 2 diabetes who were assigned to metformin required supplemental insulin (Am J Perinatol. 2013;30[6]:483-90). The study also found, however, that women treated with metformin had significantly fewer episodes of hypoglycemia, compared with women using insulin (0% vs. 36%, respectively) and fewer reports of glucose values less than 60 mg/dL (7.1% vs. 50%).

“I don’t consider this [need for supplemental insulin] ‘metformin failure,’ because studies that use metformin as monotherapy and that [show some patients] ultimately requiring insulin support ... also show that these women need less insulin,” she said. “What’s the risk of insulin alone? Hypoglycemia. So using less insulin could be a good thing.”

Other research suggests there may be less maternal weight gain, less neonatal hypoglycemia, fewer neonatal complications, and improved maternal glycemic control in patients treated with metformin, alone or with add-on insulin, than with insulin alone. “We’re starting to get a sense in the literature that, at least in the [pregnant] population with type 2 diabetes, there may be a role for metformin,” said Dr. Boggess, professor and program director for maternal-fetal medicine at the university.

* This article was updated 1/2/2020.

The Department of Health & Human Services is taking the first steps in allowing drugs to be imported into the United States.

Wikimedia Commons/WWsgConnect/CC-SA 4.0

HHS proposes to offer two different pathways for importation: One allowing states to design programs to import certain drugs directly from Canada and another allowing manufacturers to obtain a new National Drug Code (NDC) number to import their own Food and Drug Administration–approved products manufactured outside of the United States.

“The importation proposals we are rolling out ... are a historic step forward in efforts to bring down drug prices and out-of-pocket costs,” HHS Secretary Alex Azar said during a Dec. 17, 2019, press conference. “New pathways for importation can move us toward a more open and competitive marketplace that supplies American patients with safe, effective, affordable prescription drugs.”

The proposals were made public on Dec. 18, the day the House Rules committee was scheduled to vote on impeaching President Trump.

He emphasized that these proposals “are both important steps in advancing the FDA’s safe-importation action plan, [which] aims to insure that importation is done in a way that prioritizes safety and includes elements to help insure importation does not put patients or the U.S. drug supply chain at risk.”

The pathway for states to import drugs from Canada will be proposed through the federal regulatory process. The notice of proposed rulemaking, which implements authority for FDA regulation of importation granted in the Medicare Modernization Act of 2003, will outline a process by which states, potentially working with wholesalers and/or pharmacies, will submit proposals for FDA review and approval on how they would implement an importation program.

Only certain drugs would be eligible for importation from Canada under this proposal. The drugs would need to be approved in Canada and, except for Canadian labeling, need to meet the conditions of an FDA-approved new drug application or abbreviated new drug application.

Controlled substances, biologics, intravenously injected drugs, drugs with a risk evaluation and management strategy, and drugs injected into the spinal column or eye would be excluded from importation.

Drugs coming in from Canada would be relabeled with U.S.-approved labels and would be subject to testing to ensure they are authentic, not degraded, and compliant with U.S. standards.

States would be required to show that importing drugs poses no additional risk in public health and safety and it would result in the reduction of costs, according to information provided by HHS.

Many of the most expensive drugs, as well as insulins, would not be eligible for importation under this pathway, Mr. Azar acknowledged, adding that “I would envision that as we demonstrate the safety as well as the cost savings from this pathway, [this could serve as] a pilot and a proof of concept that Congress could then look to and potentially take up for more complex molecules that involve cold-chain storage and more complex distribution channels.”

The proposed regulations do not offer any estimates on how much savings could be achieved. He said that there is no way to estimate which states might develop importation plans and how those plans might work.

The second proposed pathway would involve FDA guidance to manufacturers allowing them to import their own FDA-approved products manufactured abroad. Under this proposal, there would be no restriction on which type or kind of FDA-approved product to be imported.

“The FDA has become aware that manufacturers of some brand-name drugs want to offer their drugs at lower costs in the U.S. market but, due to certain challenges in the private market, are not readily [able] to do so without obtaining a different national drug code for their drugs,” Adm. Brett Giroir, MD, HHS assistant secretary for health, said during the press conference.

Obtaining a separate NDC for imported drugs could address the challenges, particularly those posed by the incentives to raise list prices and offer higher rebates to pharmacy benefit managers, Mr. Azar said.

The draft guidance outlines procedures manufacturers could follow to get that NDC for those products and how manufacturers can demonstrate that these products meet U.S. regulatory standards. Products imported in this pathway could be made available to patients in hospitals, physician offices, and pharmacies. Generic drugs are not part of this guidance, but the proposed guidance asked for feedback on whether a similar approach is needed for generic products.

“This would potentially allow for the sale of these drugs at lower prices than currently offered to American consumers, giving drugmakers new flexibility to reduce list prices,” Mr. Azar said.

The proposed regulation on state-level importation will have a 75-day comment period from the day it is published in the Federal Register, and Mr. Azar said that the FDA is committing resources to getting the comments analyzed and reflected in the final rule.

“We will be moving as quickly as we possibly can,” Mr. Azar said, adding that the FDA guidance to manufacturers may move more quickly through its approval process because it is not a formal rule.

[email protected]

The Department of Health & Human Services is taking the first steps in allowing drugs to be imported into the United States.

Wikimedia Commons/WWsgConnect/CC-SA 4.0

HHS proposes to offer two different pathways for importation: One allowing states to design programs to import certain drugs directly from Canada and another allowing manufacturers to obtain a new National Drug Code (NDC) number to import their own Food and Drug Administration–approved products manufactured outside of the United States.

“The importation proposals we are rolling out ... are a historic step forward in efforts to bring down drug prices and out-of-pocket costs,” HHS Secretary Alex Azar said during a Dec. 17, 2019, press conference. “New pathways for importation can move us toward a more open and competitive marketplace that supplies American patients with safe, effective, affordable prescription drugs.”

The proposals were made public on Dec. 18, the day the House Rules committee was scheduled to vote on impeaching President Trump.

He emphasized that these proposals “are both important steps in advancing the FDA’s safe-importation action plan, [which] aims to insure that importation is done in a way that prioritizes safety and includes elements to help insure importation does not put patients or the U.S. drug supply chain at risk.”

The pathway for states to import drugs from Canada will be proposed through the federal regulatory process. The notice of proposed rulemaking, which implements authority for FDA regulation of importation granted in the Medicare Modernization Act of 2003, will outline a process by which states, potentially working with wholesalers and/or pharmacies, will submit proposals for FDA review and approval on how they would implement an importation program.

Only certain drugs would be eligible for importation from Canada under this proposal. The drugs would need to be approved in Canada and, except for Canadian labeling, need to meet the conditions of an FDA-approved new drug application or abbreviated new drug application.

Controlled substances, biologics, intravenously injected drugs, drugs with a risk evaluation and management strategy, and drugs injected into the spinal column or eye would be excluded from importation.

Drugs coming in from Canada would be relabeled with U.S.-approved labels and would be subject to testing to ensure they are authentic, not degraded, and compliant with U.S. standards.

States would be required to show that importing drugs poses no additional risk in public health and safety and it would result in the reduction of costs, according to information provided by HHS.

Many of the most expensive drugs, as well as insulins, would not be eligible for importation under this pathway, Mr. Azar acknowledged, adding that “I would envision that as we demonstrate the safety as well as the cost savings from this pathway, [this could serve as] a pilot and a proof of concept that Congress could then look to and potentially take up for more complex molecules that involve cold-chain storage and more complex distribution channels.”

The proposed regulations do not offer any estimates on how much savings could be achieved. He said that there is no way to estimate which states might develop importation plans and how those plans might work.

The second proposed pathway would involve FDA guidance to manufacturers allowing them to import their own FDA-approved products manufactured abroad. Under this proposal, there would be no restriction on which type or kind of FDA-approved product to be imported.

“The FDA has become aware that manufacturers of some brand-name drugs want to offer their drugs at lower costs in the U.S. market but, due to certain challenges in the private market, are not readily [able] to do so without obtaining a different national drug code for their drugs,” Adm. Brett Giroir, MD, HHS assistant secretary for health, said during the press conference.

Obtaining a separate NDC for imported drugs could address the challenges, particularly those posed by the incentives to raise list prices and offer higher rebates to pharmacy benefit managers, Mr. Azar said.

The draft guidance outlines procedures manufacturers could follow to get that NDC for those products and how manufacturers can demonstrate that these products meet U.S. regulatory standards. Products imported in this pathway could be made available to patients in hospitals, physician offices, and pharmacies. Generic drugs are not part of this guidance, but the proposed guidance asked for feedback on whether a similar approach is needed for generic products.

“This would potentially allow for the sale of these drugs at lower prices than currently offered to American consumers, giving drugmakers new flexibility to reduce list prices,” Mr. Azar said.

The proposed regulation on state-level importation will have a 75-day comment period from the day it is published in the Federal Register, and Mr. Azar said that the FDA is committing resources to getting the comments analyzed and reflected in the final rule.

“We will be moving as quickly as we possibly can,” Mr. Azar said, adding that the FDA guidance to manufacturers may move more quickly through its approval process because it is not a formal rule.

[email protected]

The Department of Health & Human Services is taking the first steps in allowing drugs to be imported into the United States.

Wikimedia Commons/WWsgConnect/CC-SA 4.0

HHS proposes to offer two different pathways for importation: One allowing states to design programs to import certain drugs directly from Canada and another allowing manufacturers to obtain a new National Drug Code (NDC) number to import their own Food and Drug Administration–approved products manufactured outside of the United States.

“The importation proposals we are rolling out ... are a historic step forward in efforts to bring down drug prices and out-of-pocket costs,” HHS Secretary Alex Azar said during a Dec. 17, 2019, press conference. “New pathways for importation can move us toward a more open and competitive marketplace that supplies American patients with safe, effective, affordable prescription drugs.”

The proposals were made public on Dec. 18, the day the House Rules committee was scheduled to vote on impeaching President Trump.

He emphasized that these proposals “are both important steps in advancing the FDA’s safe-importation action plan, [which] aims to insure that importation is done in a way that prioritizes safety and includes elements to help insure importation does not put patients or the U.S. drug supply chain at risk.”

The pathway for states to import drugs from Canada will be proposed through the federal regulatory process. The notice of proposed rulemaking, which implements authority for FDA regulation of importation granted in the Medicare Modernization Act of 2003, will outline a process by which states, potentially working with wholesalers and/or pharmacies, will submit proposals for FDA review and approval on how they would implement an importation program.

Only certain drugs would be eligible for importation from Canada under this proposal. The drugs would need to be approved in Canada and, except for Canadian labeling, need to meet the conditions of an FDA-approved new drug application or abbreviated new drug application.

Controlled substances, biologics, intravenously injected drugs, drugs with a risk evaluation and management strategy, and drugs injected into the spinal column or eye would be excluded from importation.

Drugs coming in from Canada would be relabeled with U.S.-approved labels and would be subject to testing to ensure they are authentic, not degraded, and compliant with U.S. standards.

States would be required to show that importing drugs poses no additional risk in public health and safety and it would result in the reduction of costs, according to information provided by HHS.

Many of the most expensive drugs, as well as insulins, would not be eligible for importation under this pathway, Mr. Azar acknowledged, adding that “I would envision that as we demonstrate the safety as well as the cost savings from this pathway, [this could serve as] a pilot and a proof of concept that Congress could then look to and potentially take up for more complex molecules that involve cold-chain storage and more complex distribution channels.”

The proposed regulations do not offer any estimates on how much savings could be achieved. He said that there is no way to estimate which states might develop importation plans and how those plans might work.

The second proposed pathway would involve FDA guidance to manufacturers allowing them to import their own FDA-approved products manufactured abroad. Under this proposal, there would be no restriction on which type or kind of FDA-approved product to be imported.

“The FDA has become aware that manufacturers of some brand-name drugs want to offer their drugs at lower costs in the U.S. market but, due to certain challenges in the private market, are not readily [able] to do so without obtaining a different national drug code for their drugs,” Adm. Brett Giroir, MD, HHS assistant secretary for health, said during the press conference.

Obtaining a separate NDC for imported drugs could address the challenges, particularly those posed by the incentives to raise list prices and offer higher rebates to pharmacy benefit managers, Mr. Azar said.

The draft guidance outlines procedures manufacturers could follow to get that NDC for those products and how manufacturers can demonstrate that these products meet U.S. regulatory standards. Products imported in this pathway could be made available to patients in hospitals, physician offices, and pharmacies. Generic drugs are not part of this guidance, but the proposed guidance asked for feedback on whether a similar approach is needed for generic products.

“This would potentially allow for the sale of these drugs at lower prices than currently offered to American consumers, giving drugmakers new flexibility to reduce list prices,” Mr. Azar said.

The proposed regulation on state-level importation will have a 75-day comment period from the day it is published in the Federal Register, and Mr. Azar said that the FDA is committing resources to getting the comments analyzed and reflected in the final rule.

“We will be moving as quickly as we possibly can,” Mr. Azar said, adding that the FDA guidance to manufacturers may move more quickly through its approval process because it is not a formal rule.

[email protected]

LOS ANGELES – Patients with diabetes had significantly higher adjusted risk of bleeding, cardiovascular-related death, and poorer net outcomes, particularly those treated with insulin, a subanalysis of the ENGAGE AF-TIMI 48 trial has shown.

Doug Brunk/MDedge News

In addition, the pharmacokinetic and pharmacodynamic profile of the study drug, edoxaban – a novel oral anticoagulant drug and a direct factor Xa inhibitor – was generally similar in patients with and without diabetes.

“We know that atrial fibrillation is associated with a fivefold increased risk of stroke,” Anna Plitt, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Type 2 diabetes is associated with a twofold increased risk of stroke, and longer duration of diabetes is associated with even higher ischemic event rates. The coexistence of [atrial fibrillation] and type 2 diabetes further increases thromboembolic risk.”

Dr. Plitt, a cardiology fellow at Mount Sinai Hospital, New York, noted that, although type 2 diabetes is characterized by a prothrombotic and inflammatory state, the mechanism of action by which hyperglycemia and/or insulin resistance leads to the development of atrial fibrillation (AFib) remains unknown. “Given the complex clinical interactions between AFib and type 2 diabetes, care for these patients remains challenging,” she said. “Recommendations for anticoagulation managements vary based on the presence of additional risk factors and which guidelines are followed.”

In the ENGAGE AF-TIMI 48 trial, 21,105 patients with documented AFib within the previous 12 months were randomized to standard-care warfarin or high-dose edoxaban (60 mg daily) or low-dose edoxaban (30 mg daily). The edoxaban dose was reduced by 50% if creatinine clearance reached 30-50 mL/min, patient weight reached 60 kg or less, or there was concomitant use of a P-glycoprotein inhibitor (N Engl J Med. 2013;369:2093-104). The median follow-up was 2.8 years, and the primary efficacy endpoint was stroke or systemic embolic events (SEEs). The primary safety endpoint was major bleeding, as defined by the International Society on Thrombosis and Haemostasis criteria.

The findings showed that edoxaban was noninferior to warfarin in preventing stroke/SEEs. It also significantly reduced major bleeding, cardiovascular death, and net outcomes. “Therefore, the higher dose of edoxaban was approved globally for treating patients with AFib,” Dr. Plitt said. “The lower-dose regimen was not approved because there was less protection from ischemic stroke, compared with warfarin.”

For the current subanalysis, Dr. Plitt and colleagues set out to further evaluate outcomes of patients enrolled in the ENGAGE AF-TIMI 48 trial, excluding those who were in the low-dose edoxaban group. The presence or absence of diabetes was determined by the local investigator at randomization. The investigators further stratified patients into insulin-treated and non–insulin treated groups and used multivariate Cox regression models to adjust for baseline characteristics across the groups stratified by diabetes status. Next, they analyzed edoxaban concentration, anti–factor Xa activity, and international normalized ratio data and compared outcomes of high-dose edoxaban with those of warfarin.

The primary endpoint and the primary safety endpoint of interest were the same as in the main ENGAGE AF-TIMI 48 trial. Key secondary endpoints included in the subanalysis were cardiovascular death, stroke/SEE, major adverse cardiovascular events (MACE, a composite of myocardial infarction, stroke, SEE, or death because of cardiovascular cause or bleeding), and all-cause death.

In all, 7,624 of the 21,105 patients in the ENGAGE AF-TIMI 48 trial had diabetes, for a rate of 36%. Most of the patients with diabetes did not require insulin (30%), while 6% did. There were fewer female patients with diabetes than without (37% vs. 39%, respectively). Of note was that history of prior stroke/transient ischemic attack was higher in the no-diabetes group than in the diabetes group (33% vs. 21%), as was congestive heart failure (63% vs. 48%).

The mean CHA2DS2-VASc score for predicting thromboembolic risk (0, low risk; greater than 1, high risk) was 4.6 in the diabetes group and 4.2 in the no-diabetes group. When diabetes was not included in the score, the mean CHA2DS2-VASc score was 3.6 in the diabetes group. “Because the trial entry criteria required a minimum CHADS2 score of 2, patients without diabetes were enriched with stroke risk factors other than diabetes,” Dr. Plitt said.

Adjusted outcomes from the subanalysis showed that the risk of stroke/SEE was similar between patients with and without diabetes (hazard ratio, 1.08). However, patients with diabetes were at higher adjusted risk for cardiovascular death than patients without diabetes (HR, 1.29), MACE (HR, 1.28), major bleed (HR, 1.28), and the net outcome of stroke, SEE, major bleed, or all-cause death (HR, 1.25).

The researchers also analyzed the pharmacodynamic and pharmacokinetic data of high-dose edoxaban, stratified by diabetes status. They found that the parameters were generally similar between patients with and without diabetes, including trough concentrations of edoxaban (34.3 and 37.2 ng/mL, respectively; P = .04), trough exogenous anti–factor Xa activity (0.59 and 0.68 IU/mL; P = .11), and the percentage change from baseline in the peak endogenous anti–factor Xa activity (P = .66). The percentage changes from baseline of the trough endogenous anti–factor Xa activity was slightly lower in patients with diabetes, compared with patients without diabetes (P less than .001). “However, these modest differences between the two groups are of unclear clinical significance,” Dr. Plitt said.

Results from the main ENGAGE AF-TIMI 48 showed that the rates of stroke/SEE were reduced by 13% on high-dose edoxaban. However, the subanalysis found no significant effect modification in the reduction in stroke/SEE with edoxaban, compared with warfarin, when stratified by diabetes status (reductions of 16% vs. 7% in the no-diabetes and diabetes groups, respectively; P for interaction = .54). The researchers also observed similar reductions with edoxaban in the risks of secondary outcomes when patients were stratified by diabetes status.

In another finding, patients with diabetes who were treated with insulin were at a higher adjusted risk for all outcomes, compared with those with diabetes who were not treated with insulin. This included stroke/SEE (HR, 1.44), cardiovascular-related death (HR, 1.83), MACE (HR, 1.78), major bleed (HR, 1.31), and net outcome (HR, 1.57).

Next, the researchers compared the study endpoints of high-dose edoxaban and warfarin, with and without insulin. “None of the efficacy, safety, or net outcomes demonstrated evidence of treatment effect modification related to the use of insulin among [patients with diabetes],” she said.

Dr. Plitt disclosed having received honoraria for educational activities from Bristol-Myers Squibb.

[email protected]

LOS ANGELES – Patients with diabetes had significantly higher adjusted risk of bleeding, cardiovascular-related death, and poorer net outcomes, particularly those treated with insulin, a subanalysis of the ENGAGE AF-TIMI 48 trial has shown.

Doug Brunk/MDedge News

In addition, the pharmacokinetic and pharmacodynamic profile of the study drug, edoxaban – a novel oral anticoagulant drug and a direct factor Xa inhibitor – was generally similar in patients with and without diabetes.

“We know that atrial fibrillation is associated with a fivefold increased risk of stroke,” Anna Plitt, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Type 2 diabetes is associated with a twofold increased risk of stroke, and longer duration of diabetes is associated with even higher ischemic event rates. The coexistence of [atrial fibrillation] and type 2 diabetes further increases thromboembolic risk.”

Dr. Plitt, a cardiology fellow at Mount Sinai Hospital, New York, noted that, although type 2 diabetes is characterized by a prothrombotic and inflammatory state, the mechanism of action by which hyperglycemia and/or insulin resistance leads to the development of atrial fibrillation (AFib) remains unknown. “Given the complex clinical interactions between AFib and type 2 diabetes, care for these patients remains challenging,” she said. “Recommendations for anticoagulation managements vary based on the presence of additional risk factors and which guidelines are followed.”

In the ENGAGE AF-TIMI 48 trial, 21,105 patients with documented AFib within the previous 12 months were randomized to standard-care warfarin or high-dose edoxaban (60 mg daily) or low-dose edoxaban (30 mg daily). The edoxaban dose was reduced by 50% if creatinine clearance reached 30-50 mL/min, patient weight reached 60 kg or less, or there was concomitant use of a P-glycoprotein inhibitor (N Engl J Med. 2013;369:2093-104). The median follow-up was 2.8 years, and the primary efficacy endpoint was stroke or systemic embolic events (SEEs). The primary safety endpoint was major bleeding, as defined by the International Society on Thrombosis and Haemostasis criteria.

The findings showed that edoxaban was noninferior to warfarin in preventing stroke/SEEs. It also significantly reduced major bleeding, cardiovascular death, and net outcomes. “Therefore, the higher dose of edoxaban was approved globally for treating patients with AFib,” Dr. Plitt said. “The lower-dose regimen was not approved because there was less protection from ischemic stroke, compared with warfarin.”

For the current subanalysis, Dr. Plitt and colleagues set out to further evaluate outcomes of patients enrolled in the ENGAGE AF-TIMI 48 trial, excluding those who were in the low-dose edoxaban group. The presence or absence of diabetes was determined by the local investigator at randomization. The investigators further stratified patients into insulin-treated and non–insulin treated groups and used multivariate Cox regression models to adjust for baseline characteristics across the groups stratified by diabetes status. Next, they analyzed edoxaban concentration, anti–factor Xa activity, and international normalized ratio data and compared outcomes of high-dose edoxaban with those of warfarin.

The primary endpoint and the primary safety endpoint of interest were the same as in the main ENGAGE AF-TIMI 48 trial. Key secondary endpoints included in the subanalysis were cardiovascular death, stroke/SEE, major adverse cardiovascular events (MACE, a composite of myocardial infarction, stroke, SEE, or death because of cardiovascular cause or bleeding), and all-cause death.

In all, 7,624 of the 21,105 patients in the ENGAGE AF-TIMI 48 trial had diabetes, for a rate of 36%. Most of the patients with diabetes did not require insulin (30%), while 6% did. There were fewer female patients with diabetes than without (37% vs. 39%, respectively). Of note was that history of prior stroke/transient ischemic attack was higher in the no-diabetes group than in the diabetes group (33% vs. 21%), as was congestive heart failure (63% vs. 48%).

The mean CHA2DS2-VASc score for predicting thromboembolic risk (0, low risk; greater than 1, high risk) was 4.6 in the diabetes group and 4.2 in the no-diabetes group. When diabetes was not included in the score, the mean CHA2DS2-VASc score was 3.6 in the diabetes group. “Because the trial entry criteria required a minimum CHADS2 score of 2, patients without diabetes were enriched with stroke risk factors other than diabetes,” Dr. Plitt said.

Adjusted outcomes from the subanalysis showed that the risk of stroke/SEE was similar between patients with and without diabetes (hazard ratio, 1.08). However, patients with diabetes were at higher adjusted risk for cardiovascular death than patients without diabetes (HR, 1.29), MACE (HR, 1.28), major bleed (HR, 1.28), and the net outcome of stroke, SEE, major bleed, or all-cause death (HR, 1.25).

The researchers also analyzed the pharmacodynamic and pharmacokinetic data of high-dose edoxaban, stratified by diabetes status. They found that the parameters were generally similar between patients with and without diabetes, including trough concentrations of edoxaban (34.3 and 37.2 ng/mL, respectively; P = .04), trough exogenous anti–factor Xa activity (0.59 and 0.68 IU/mL; P = .11), and the percentage change from baseline in the peak endogenous anti–factor Xa activity (P = .66). The percentage changes from baseline of the trough endogenous anti–factor Xa activity was slightly lower in patients with diabetes, compared with patients without diabetes (P less than .001). “However, these modest differences between the two groups are of unclear clinical significance,” Dr. Plitt said.

Results from the main ENGAGE AF-TIMI 48 showed that the rates of stroke/SEE were reduced by 13% on high-dose edoxaban. However, the subanalysis found no significant effect modification in the reduction in stroke/SEE with edoxaban, compared with warfarin, when stratified by diabetes status (reductions of 16% vs. 7% in the no-diabetes and diabetes groups, respectively; P for interaction = .54). The researchers also observed similar reductions with edoxaban in the risks of secondary outcomes when patients were stratified by diabetes status.

In another finding, patients with diabetes who were treated with insulin were at a higher adjusted risk for all outcomes, compared with those with diabetes who were not treated with insulin. This included stroke/SEE (HR, 1.44), cardiovascular-related death (HR, 1.83), MACE (HR, 1.78), major bleed (HR, 1.31), and net outcome (HR, 1.57).

Next, the researchers compared the study endpoints of high-dose edoxaban and warfarin, with and without insulin. “None of the efficacy, safety, or net outcomes demonstrated evidence of treatment effect modification related to the use of insulin among [patients with diabetes],” she said.

Dr. Plitt disclosed having received honoraria for educational activities from Bristol-Myers Squibb.

[email protected]

LOS ANGELES – Patients with diabetes had significantly higher adjusted risk of bleeding, cardiovascular-related death, and poorer net outcomes, particularly those treated with insulin, a subanalysis of the ENGAGE AF-TIMI 48 trial has shown.

Doug Brunk/MDedge News

In addition, the pharmacokinetic and pharmacodynamic profile of the study drug, edoxaban – a novel oral anticoagulant drug and a direct factor Xa inhibitor – was generally similar in patients with and without diabetes.

“We know that atrial fibrillation is associated with a fivefold increased risk of stroke,” Anna Plitt, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Type 2 diabetes is associated with a twofold increased risk of stroke, and longer duration of diabetes is associated with even higher ischemic event rates. The coexistence of [atrial fibrillation] and type 2 diabetes further increases thromboembolic risk.”

Dr. Plitt, a cardiology fellow at Mount Sinai Hospital, New York, noted that, although type 2 diabetes is characterized by a prothrombotic and inflammatory state, the mechanism of action by which hyperglycemia and/or insulin resistance leads to the development of atrial fibrillation (AFib) remains unknown. “Given the complex clinical interactions between AFib and type 2 diabetes, care for these patients remains challenging,” she said. “Recommendations for anticoagulation managements vary based on the presence of additional risk factors and which guidelines are followed.”

In the ENGAGE AF-TIMI 48 trial, 21,105 patients with documented AFib within the previous 12 months were randomized to standard-care warfarin or high-dose edoxaban (60 mg daily) or low-dose edoxaban (30 mg daily). The edoxaban dose was reduced by 50% if creatinine clearance reached 30-50 mL/min, patient weight reached 60 kg or less, or there was concomitant use of a P-glycoprotein inhibitor (N Engl J Med. 2013;369:2093-104). The median follow-up was 2.8 years, and the primary efficacy endpoint was stroke or systemic embolic events (SEEs). The primary safety endpoint was major bleeding, as defined by the International Society on Thrombosis and Haemostasis criteria.

The findings showed that edoxaban was noninferior to warfarin in preventing stroke/SEEs. It also significantly reduced major bleeding, cardiovascular death, and net outcomes. “Therefore, the higher dose of edoxaban was approved globally for treating patients with AFib,” Dr. Plitt said. “The lower-dose regimen was not approved because there was less protection from ischemic stroke, compared with warfarin.”

For the current subanalysis, Dr. Plitt and colleagues set out to further evaluate outcomes of patients enrolled in the ENGAGE AF-TIMI 48 trial, excluding those who were in the low-dose edoxaban group. The presence or absence of diabetes was determined by the local investigator at randomization. The investigators further stratified patients into insulin-treated and non–insulin treated groups and used multivariate Cox regression models to adjust for baseline characteristics across the groups stratified by diabetes status. Next, they analyzed edoxaban concentration, anti–factor Xa activity, and international normalized ratio data and compared outcomes of high-dose edoxaban with those of warfarin.

The primary endpoint and the primary safety endpoint of interest were the same as in the main ENGAGE AF-TIMI 48 trial. Key secondary endpoints included in the subanalysis were cardiovascular death, stroke/SEE, major adverse cardiovascular events (MACE, a composite of myocardial infarction, stroke, SEE, or death because of cardiovascular cause or bleeding), and all-cause death.

In all, 7,624 of the 21,105 patients in the ENGAGE AF-TIMI 48 trial had diabetes, for a rate of 36%. Most of the patients with diabetes did not require insulin (30%), while 6% did. There were fewer female patients with diabetes than without (37% vs. 39%, respectively). Of note was that history of prior stroke/transient ischemic attack was higher in the no-diabetes group than in the diabetes group (33% vs. 21%), as was congestive heart failure (63% vs. 48%).

The mean CHA2DS2-VASc score for predicting thromboembolic risk (0, low risk; greater than 1, high risk) was 4.6 in the diabetes group and 4.2 in the no-diabetes group. When diabetes was not included in the score, the mean CHA2DS2-VASc score was 3.6 in the diabetes group. “Because the trial entry criteria required a minimum CHADS2 score of 2, patients without diabetes were enriched with stroke risk factors other than diabetes,” Dr. Plitt said.

Adjusted outcomes from the subanalysis showed that the risk of stroke/SEE was similar between patients with and without diabetes (hazard ratio, 1.08). However, patients with diabetes were at higher adjusted risk for cardiovascular death than patients without diabetes (HR, 1.29), MACE (HR, 1.28), major bleed (HR, 1.28), and the net outcome of stroke, SEE, major bleed, or all-cause death (HR, 1.25).

The researchers also analyzed the pharmacodynamic and pharmacokinetic data of high-dose edoxaban, stratified by diabetes status. They found that the parameters were generally similar between patients with and without diabetes, including trough concentrations of edoxaban (34.3 and 37.2 ng/mL, respectively; P = .04), trough exogenous anti–factor Xa activity (0.59 and 0.68 IU/mL; P = .11), and the percentage change from baseline in the peak endogenous anti–factor Xa activity (P = .66). The percentage changes from baseline of the trough endogenous anti–factor Xa activity was slightly lower in patients with diabetes, compared with patients without diabetes (P less than .001). “However, these modest differences between the two groups are of unclear clinical significance,” Dr. Plitt said.

Results from the main ENGAGE AF-TIMI 48 showed that the rates of stroke/SEE were reduced by 13% on high-dose edoxaban. However, the subanalysis found no significant effect modification in the reduction in stroke/SEE with edoxaban, compared with warfarin, when stratified by diabetes status (reductions of 16% vs. 7% in the no-diabetes and diabetes groups, respectively; P for interaction = .54). The researchers also observed similar reductions with edoxaban in the risks of secondary outcomes when patients were stratified by diabetes status.

In another finding, patients with diabetes who were treated with insulin were at a higher adjusted risk for all outcomes, compared with those with diabetes who were not treated with insulin. This included stroke/SEE (HR, 1.44), cardiovascular-related death (HR, 1.83), MACE (HR, 1.78), major bleed (HR, 1.31), and net outcome (HR, 1.57).

Next, the researchers compared the study endpoints of high-dose edoxaban and warfarin, with and without insulin. “None of the efficacy, safety, or net outcomes demonstrated evidence of treatment effect modification related to the use of insulin among [patients with diabetes],” she said.

Dr. Plitt disclosed having received honoraria for educational activities from Bristol-Myers Squibb.

[email protected]