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Noteworthy advances in treatment and management of IBD
Although it had been thought that incidence rates of IBD were plateauing in high-incidence areas, a Danish study found a steady increase in incidence of Crohn’s disease and ulcerative colitis (UC).1 The highest increase in rates occurred in children and young adults, which will have repercussions as people get older and contribute to higher compounding prevalence. We need to get better at dealing with other health conditions as patients get older. A very large prospective Spanish study found that 42% of IBD patients scanned consecutively had MAFLD (metabolic-associated fatty liver disease) – even if they didn’t have high BMI and type 2 diabetes, suggesting that systemic inflammation in IBD contributes to the development of metabolic liver disease.2
The AGA has recently published guidelines for using biomarkers in the management of UC. Patients with very low fecal calprotectin (FCP) are unlikely to have active disease whereas FCP over 150 with significant symptoms may warrant empiric changes in treatment.3
Intestinal ultrasound is gaining wider acceptance as a noninvasive way to monitor IBD.4 In a UC study, improvement in bowel wall thickness following tofacitinib treatment correlated well with endoscopic activity.5
The majority of the presentation focused on the explosion of Food and Drug Administration–-approved medications for IBD in recent years. S1P receptor agonists, such as ozanimod and etrasimod, may work by trapping specific T-cell subsets in peripheral lymph nodes, preventing migration to intestinal tissues. Ozanimod is approved for UC. Etrasimod showed efficacy in UC with clinical remission rates of about 27% at week 12 and 32% at week 52.6,7
There has been a lot of excitement about JAK inhibitors for IBD. Upadacitinib has recently been approved for both UC and Crohn’s disease. Response rates of 73% and remission rates of 26% were seen in UC patients who had been largely biologic exposed.8 Similar results were seen in a biologic-exposed Crohn’s disease population treated with upadacitinib including in endoscopy.9 Upadacitinib was effective in maintaining remission at both 15-mg and 30-mg doses; but the higher dose had a greater effect on endoscopic endpoints.10
For Crohn’s disease, we now have risankizumab, an anti-p19/IL-23 inhibitor. Risankizumab was efficacious at inducing and maintain remission in the pivotal phase 3 studies, even with 75% of patients being biologic exposed. These studies used combined endpoints of clinical remission as well as endoscopic response.11 Guselkumab (anti-p19/IL-23) is also being studied for Crohn’s disease and early trials has appears to be efficacious.12
A head-to-head study of naive CD patients treated with ustekinumab or adalimumab (SEAVUE) showed comparable rates of clinical remission. At 52 weeks, the rates of clinical remission were quite high: >60% and endoscopic remission >30% with either therapy.13
We now have phase 3 data showing that a biologic is efficacious in patients with chronic pouchitis. The EARNEST trial demonstrated that vedolizumab has efficacy in treating pouchitis with improved clinical symptoms and endoscopy.14 Future treatment strategies may involve combinations of biologic therapies. The VEGA study showed that combining an anti-TNF, golimumab, with an anti-IL23, guselkumab, was superior than either alone with respect to clinical remission and endoscopic improvement in UC.15 We will see more studies combining therapies with diverse mechanisms of action.
In summary, there have been many noteworthy advances in treatment and management of IBD in the past year.
DDW is sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE) and The Society for Surgery of the Alimentary Tract (SSAT).
Dr. Abreu is director of the Crohn’s and Colitis Center and professor of medicine, microbiology, and immunology at the University of Miami. She is president-elect of AGA. Dr. Allegretti is director of the Crohn’s and Colitis Center and director of the fecal microbiota transplant program at Brigham and Women’s Hospital, Boston. She is associate professor of medicine at Harvard Medical School, Boston. Dr. Loftus is the Maxine and Jack Zarrow Family Professor of Gastroenterology, codirector of the advanced IBD fellowship in the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn. Dr. Ungaro is associate professor of medicine at the Icahn School of Medicine at Mount Sinai, New York.
References
1. Agrawal M et al. Gastroenterology. 2022;163(6):1547-54.e5.
2. Rodriguez-Duque JC et al. Clin Gastroenterol Hepatol. 2023;21(2):406-14.e7.
3. Singh S, et al. Gastroenterology. 2023;164(3):344-72.
4. de Voogd F et al. Gastroenterology. 2022;163(6):1569-81.
5. Sandborn WJ et al. N Engl J Med. 2017;376(18):1723-36.
6. Sandborn WJ et al. N Engl J Med. 2021;385(14):1280-91.
7. Sandborn WJ et al. Lancet. 2023 Mar 25;401(10381):1000]. Lancet. 2023;401(10383):1159-71.
8. Danese S et al. Lancet. 2022 Sep 24;400(10357):996]. Lancet. 2022;399(10341):2113-28.
9. Loftus EV Jr et al. N Engl J Med. 2023 May 25;388(21):1966-80.
10. Panes J et al. Am J Gastroenterol 2022;117(S10). Abstract S37.
11. D’Haens G, et al. Lancet. 2022;399(10340):2015-30
12. Sandborn WJ et al. Gastroenterology. 2022;162(6):1650-64.e8.
13. Sands BE, et al. Lancet. 2022;399(10342):2200-11.
14. Travis S et al. N Engl J Med. 2023;388(13):1191-1200.
15. Feagan BG et al. Lancet Gastroenterol Hepatol. 2023;8(4):307-20.
Although it had been thought that incidence rates of IBD were plateauing in high-incidence areas, a Danish study found a steady increase in incidence of Crohn’s disease and ulcerative colitis (UC).1 The highest increase in rates occurred in children and young adults, which will have repercussions as people get older and contribute to higher compounding prevalence. We need to get better at dealing with other health conditions as patients get older. A very large prospective Spanish study found that 42% of IBD patients scanned consecutively had MAFLD (metabolic-associated fatty liver disease) – even if they didn’t have high BMI and type 2 diabetes, suggesting that systemic inflammation in IBD contributes to the development of metabolic liver disease.2
The AGA has recently published guidelines for using biomarkers in the management of UC. Patients with very low fecal calprotectin (FCP) are unlikely to have active disease whereas FCP over 150 with significant symptoms may warrant empiric changes in treatment.3
Intestinal ultrasound is gaining wider acceptance as a noninvasive way to monitor IBD.4 In a UC study, improvement in bowel wall thickness following tofacitinib treatment correlated well with endoscopic activity.5
The majority of the presentation focused on the explosion of Food and Drug Administration–-approved medications for IBD in recent years. S1P receptor agonists, such as ozanimod and etrasimod, may work by trapping specific T-cell subsets in peripheral lymph nodes, preventing migration to intestinal tissues. Ozanimod is approved for UC. Etrasimod showed efficacy in UC with clinical remission rates of about 27% at week 12 and 32% at week 52.6,7
There has been a lot of excitement about JAK inhibitors for IBD. Upadacitinib has recently been approved for both UC and Crohn’s disease. Response rates of 73% and remission rates of 26% were seen in UC patients who had been largely biologic exposed.8 Similar results were seen in a biologic-exposed Crohn’s disease population treated with upadacitinib including in endoscopy.9 Upadacitinib was effective in maintaining remission at both 15-mg and 30-mg doses; but the higher dose had a greater effect on endoscopic endpoints.10
For Crohn’s disease, we now have risankizumab, an anti-p19/IL-23 inhibitor. Risankizumab was efficacious at inducing and maintain remission in the pivotal phase 3 studies, even with 75% of patients being biologic exposed. These studies used combined endpoints of clinical remission as well as endoscopic response.11 Guselkumab (anti-p19/IL-23) is also being studied for Crohn’s disease and early trials has appears to be efficacious.12
A head-to-head study of naive CD patients treated with ustekinumab or adalimumab (SEAVUE) showed comparable rates of clinical remission. At 52 weeks, the rates of clinical remission were quite high: >60% and endoscopic remission >30% with either therapy.13
We now have phase 3 data showing that a biologic is efficacious in patients with chronic pouchitis. The EARNEST trial demonstrated that vedolizumab has efficacy in treating pouchitis with improved clinical symptoms and endoscopy.14 Future treatment strategies may involve combinations of biologic therapies. The VEGA study showed that combining an anti-TNF, golimumab, with an anti-IL23, guselkumab, was superior than either alone with respect to clinical remission and endoscopic improvement in UC.15 We will see more studies combining therapies with diverse mechanisms of action.
In summary, there have been many noteworthy advances in treatment and management of IBD in the past year.
DDW is sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE) and The Society for Surgery of the Alimentary Tract (SSAT).
Dr. Abreu is director of the Crohn’s and Colitis Center and professor of medicine, microbiology, and immunology at the University of Miami. She is president-elect of AGA. Dr. Allegretti is director of the Crohn’s and Colitis Center and director of the fecal microbiota transplant program at Brigham and Women’s Hospital, Boston. She is associate professor of medicine at Harvard Medical School, Boston. Dr. Loftus is the Maxine and Jack Zarrow Family Professor of Gastroenterology, codirector of the advanced IBD fellowship in the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn. Dr. Ungaro is associate professor of medicine at the Icahn School of Medicine at Mount Sinai, New York.
References
1. Agrawal M et al. Gastroenterology. 2022;163(6):1547-54.e5.
2. Rodriguez-Duque JC et al. Clin Gastroenterol Hepatol. 2023;21(2):406-14.e7.
3. Singh S, et al. Gastroenterology. 2023;164(3):344-72.
4. de Voogd F et al. Gastroenterology. 2022;163(6):1569-81.
5. Sandborn WJ et al. N Engl J Med. 2017;376(18):1723-36.
6. Sandborn WJ et al. N Engl J Med. 2021;385(14):1280-91.
7. Sandborn WJ et al. Lancet. 2023 Mar 25;401(10381):1000]. Lancet. 2023;401(10383):1159-71.
8. Danese S et al. Lancet. 2022 Sep 24;400(10357):996]. Lancet. 2022;399(10341):2113-28.
9. Loftus EV Jr et al. N Engl J Med. 2023 May 25;388(21):1966-80.
10. Panes J et al. Am J Gastroenterol 2022;117(S10). Abstract S37.
11. D’Haens G, et al. Lancet. 2022;399(10340):2015-30
12. Sandborn WJ et al. Gastroenterology. 2022;162(6):1650-64.e8.
13. Sands BE, et al. Lancet. 2022;399(10342):2200-11.
14. Travis S et al. N Engl J Med. 2023;388(13):1191-1200.
15. Feagan BG et al. Lancet Gastroenterol Hepatol. 2023;8(4):307-20.
Although it had been thought that incidence rates of IBD were plateauing in high-incidence areas, a Danish study found a steady increase in incidence of Crohn’s disease and ulcerative colitis (UC).1 The highest increase in rates occurred in children and young adults, which will have repercussions as people get older and contribute to higher compounding prevalence. We need to get better at dealing with other health conditions as patients get older. A very large prospective Spanish study found that 42% of IBD patients scanned consecutively had MAFLD (metabolic-associated fatty liver disease) – even if they didn’t have high BMI and type 2 diabetes, suggesting that systemic inflammation in IBD contributes to the development of metabolic liver disease.2
The AGA has recently published guidelines for using biomarkers in the management of UC. Patients with very low fecal calprotectin (FCP) are unlikely to have active disease whereas FCP over 150 with significant symptoms may warrant empiric changes in treatment.3
Intestinal ultrasound is gaining wider acceptance as a noninvasive way to monitor IBD.4 In a UC study, improvement in bowel wall thickness following tofacitinib treatment correlated well with endoscopic activity.5
The majority of the presentation focused on the explosion of Food and Drug Administration–-approved medications for IBD in recent years. S1P receptor agonists, such as ozanimod and etrasimod, may work by trapping specific T-cell subsets in peripheral lymph nodes, preventing migration to intestinal tissues. Ozanimod is approved for UC. Etrasimod showed efficacy in UC with clinical remission rates of about 27% at week 12 and 32% at week 52.6,7
There has been a lot of excitement about JAK inhibitors for IBD. Upadacitinib has recently been approved for both UC and Crohn’s disease. Response rates of 73% and remission rates of 26% were seen in UC patients who had been largely biologic exposed.8 Similar results were seen in a biologic-exposed Crohn’s disease population treated with upadacitinib including in endoscopy.9 Upadacitinib was effective in maintaining remission at both 15-mg and 30-mg doses; but the higher dose had a greater effect on endoscopic endpoints.10
For Crohn’s disease, we now have risankizumab, an anti-p19/IL-23 inhibitor. Risankizumab was efficacious at inducing and maintain remission in the pivotal phase 3 studies, even with 75% of patients being biologic exposed. These studies used combined endpoints of clinical remission as well as endoscopic response.11 Guselkumab (anti-p19/IL-23) is also being studied for Crohn’s disease and early trials has appears to be efficacious.12
A head-to-head study of naive CD patients treated with ustekinumab or adalimumab (SEAVUE) showed comparable rates of clinical remission. At 52 weeks, the rates of clinical remission were quite high: >60% and endoscopic remission >30% with either therapy.13
We now have phase 3 data showing that a biologic is efficacious in patients with chronic pouchitis. The EARNEST trial demonstrated that vedolizumab has efficacy in treating pouchitis with improved clinical symptoms and endoscopy.14 Future treatment strategies may involve combinations of biologic therapies. The VEGA study showed that combining an anti-TNF, golimumab, with an anti-IL23, guselkumab, was superior than either alone with respect to clinical remission and endoscopic improvement in UC.15 We will see more studies combining therapies with diverse mechanisms of action.
In summary, there have been many noteworthy advances in treatment and management of IBD in the past year.
DDW is sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE) and The Society for Surgery of the Alimentary Tract (SSAT).
Dr. Abreu is director of the Crohn’s and Colitis Center and professor of medicine, microbiology, and immunology at the University of Miami. She is president-elect of AGA. Dr. Allegretti is director of the Crohn’s and Colitis Center and director of the fecal microbiota transplant program at Brigham and Women’s Hospital, Boston. She is associate professor of medicine at Harvard Medical School, Boston. Dr. Loftus is the Maxine and Jack Zarrow Family Professor of Gastroenterology, codirector of the advanced IBD fellowship in the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn. Dr. Ungaro is associate professor of medicine at the Icahn School of Medicine at Mount Sinai, New York.
References
1. Agrawal M et al. Gastroenterology. 2022;163(6):1547-54.e5.
2. Rodriguez-Duque JC et al. Clin Gastroenterol Hepatol. 2023;21(2):406-14.e7.
3. Singh S, et al. Gastroenterology. 2023;164(3):344-72.
4. de Voogd F et al. Gastroenterology. 2022;163(6):1569-81.
5. Sandborn WJ et al. N Engl J Med. 2017;376(18):1723-36.
6. Sandborn WJ et al. N Engl J Med. 2021;385(14):1280-91.
7. Sandborn WJ et al. Lancet. 2023 Mar 25;401(10381):1000]. Lancet. 2023;401(10383):1159-71.
8. Danese S et al. Lancet. 2022 Sep 24;400(10357):996]. Lancet. 2022;399(10341):2113-28.
9. Loftus EV Jr et al. N Engl J Med. 2023 May 25;388(21):1966-80.
10. Panes J et al. Am J Gastroenterol 2022;117(S10). Abstract S37.
11. D’Haens G, et al. Lancet. 2022;399(10340):2015-30
12. Sandborn WJ et al. Gastroenterology. 2022;162(6):1650-64.e8.
13. Sands BE, et al. Lancet. 2022;399(10342):2200-11.
14. Travis S et al. N Engl J Med. 2023;388(13):1191-1200.
15. Feagan BG et al. Lancet Gastroenterol Hepatol. 2023;8(4):307-20.
AT DDW 2023
Bulevirtide shows promise in chronic hepatitis D
shows an ongoing phase 3 study conducted in the United States and four other countries.
The findings were published in the New England Journal of Medicine.
Led by Heiner Wedemeyer, MD, of Hannover Medical School in Germany, the study included 150 patients with HDV, with and without compensated cirrhosis (mean age, 42 years; 57% male; 83% White). They were randomly assigned to receive 2 mg or 10 mg of bulevirtide subcutaneously daily for 144 weeks or, as a control group, receive no treatment for 48 weeks, followed by 10 mg of bulevirtide daily for 96 weeks. All patients were followed for 96 weeks after treatment ends.
For the primary endpoint, the combined viral and ALT response at week 48 was similar in the 2-mg (45%) and 10-mg (48%) groups, compared with 2% in the control group (one patient). Twelve percent of patients in the 2-mg group and 20% of patients in the 10-mg group had a clinical benefit, compared with none of the patients in the control group.
Among those with a combined response, normalization of the ALT level occurred in most patients by week 24, while the HDV RNA level continued to decline between week 24 and week 48, the authors wrote.
“This surrogate end point is considered to be a reasonably likely predictor of improved clinical outcomes in patients with HDV; however, longer-term data are needed to confirm the clinical benefit of bulevirtide,” the investigators wrote.
The results offer a glimmer of hope, Marc Ghany, MD, MHSc, of the National Institute of Diabetes and Digestive and Kidney Diseases wrote in an accompanying editorial. “The goal of HDV therapy is to improve patient survival by preventing progression to cirrhosis, liver failure, and liver cancer,” he wrote.
In safety results, headache, pruritus, fatigue, and eosinophilia were more common in the bulevirtide groups than in the control group. All adverse events were mild to moderate.
HDV infects about 5% of people with chronic HBV and relies on HBV surface antigen (HBsAg) for transmission and infectivity. Bulevirtide is derived from a region of the large envelope protein of HBsAg and irreversibly binds to the hepatocyte entry receptor for both HDV and HBV.
Bulevirtide has received conditional approval in the European Union. In 2022, the Food and Drug Administration declined to approve bulevirtide over concerns about production and delivery of the drug. There are no approved treatments for HDV in the United States.
The study was supported by Gilead Sciences. Dr. Wedemeyer disclosed research funding, acting as a consultant to, and giving paid lectures on behalf of Gilead Sciences. He and other coauthors disclosed financial relationships with Gilead and other pharmaceutical companies.
shows an ongoing phase 3 study conducted in the United States and four other countries.
The findings were published in the New England Journal of Medicine.
Led by Heiner Wedemeyer, MD, of Hannover Medical School in Germany, the study included 150 patients with HDV, with and without compensated cirrhosis (mean age, 42 years; 57% male; 83% White). They were randomly assigned to receive 2 mg or 10 mg of bulevirtide subcutaneously daily for 144 weeks or, as a control group, receive no treatment for 48 weeks, followed by 10 mg of bulevirtide daily for 96 weeks. All patients were followed for 96 weeks after treatment ends.
For the primary endpoint, the combined viral and ALT response at week 48 was similar in the 2-mg (45%) and 10-mg (48%) groups, compared with 2% in the control group (one patient). Twelve percent of patients in the 2-mg group and 20% of patients in the 10-mg group had a clinical benefit, compared with none of the patients in the control group.
Among those with a combined response, normalization of the ALT level occurred in most patients by week 24, while the HDV RNA level continued to decline between week 24 and week 48, the authors wrote.
“This surrogate end point is considered to be a reasonably likely predictor of improved clinical outcomes in patients with HDV; however, longer-term data are needed to confirm the clinical benefit of bulevirtide,” the investigators wrote.
The results offer a glimmer of hope, Marc Ghany, MD, MHSc, of the National Institute of Diabetes and Digestive and Kidney Diseases wrote in an accompanying editorial. “The goal of HDV therapy is to improve patient survival by preventing progression to cirrhosis, liver failure, and liver cancer,” he wrote.
In safety results, headache, pruritus, fatigue, and eosinophilia were more common in the bulevirtide groups than in the control group. All adverse events were mild to moderate.
HDV infects about 5% of people with chronic HBV and relies on HBV surface antigen (HBsAg) for transmission and infectivity. Bulevirtide is derived from a region of the large envelope protein of HBsAg and irreversibly binds to the hepatocyte entry receptor for both HDV and HBV.
Bulevirtide has received conditional approval in the European Union. In 2022, the Food and Drug Administration declined to approve bulevirtide over concerns about production and delivery of the drug. There are no approved treatments for HDV in the United States.
The study was supported by Gilead Sciences. Dr. Wedemeyer disclosed research funding, acting as a consultant to, and giving paid lectures on behalf of Gilead Sciences. He and other coauthors disclosed financial relationships with Gilead and other pharmaceutical companies.
shows an ongoing phase 3 study conducted in the United States and four other countries.
The findings were published in the New England Journal of Medicine.
Led by Heiner Wedemeyer, MD, of Hannover Medical School in Germany, the study included 150 patients with HDV, with and without compensated cirrhosis (mean age, 42 years; 57% male; 83% White). They were randomly assigned to receive 2 mg or 10 mg of bulevirtide subcutaneously daily for 144 weeks or, as a control group, receive no treatment for 48 weeks, followed by 10 mg of bulevirtide daily for 96 weeks. All patients were followed for 96 weeks after treatment ends.
For the primary endpoint, the combined viral and ALT response at week 48 was similar in the 2-mg (45%) and 10-mg (48%) groups, compared with 2% in the control group (one patient). Twelve percent of patients in the 2-mg group and 20% of patients in the 10-mg group had a clinical benefit, compared with none of the patients in the control group.
Among those with a combined response, normalization of the ALT level occurred in most patients by week 24, while the HDV RNA level continued to decline between week 24 and week 48, the authors wrote.
“This surrogate end point is considered to be a reasonably likely predictor of improved clinical outcomes in patients with HDV; however, longer-term data are needed to confirm the clinical benefit of bulevirtide,” the investigators wrote.
The results offer a glimmer of hope, Marc Ghany, MD, MHSc, of the National Institute of Diabetes and Digestive and Kidney Diseases wrote in an accompanying editorial. “The goal of HDV therapy is to improve patient survival by preventing progression to cirrhosis, liver failure, and liver cancer,” he wrote.
In safety results, headache, pruritus, fatigue, and eosinophilia were more common in the bulevirtide groups than in the control group. All adverse events were mild to moderate.
HDV infects about 5% of people with chronic HBV and relies on HBV surface antigen (HBsAg) for transmission and infectivity. Bulevirtide is derived from a region of the large envelope protein of HBsAg and irreversibly binds to the hepatocyte entry receptor for both HDV and HBV.
Bulevirtide has received conditional approval in the European Union. In 2022, the Food and Drug Administration declined to approve bulevirtide over concerns about production and delivery of the drug. There are no approved treatments for HDV in the United States.
The study was supported by Gilead Sciences. Dr. Wedemeyer disclosed research funding, acting as a consultant to, and giving paid lectures on behalf of Gilead Sciences. He and other coauthors disclosed financial relationships with Gilead and other pharmaceutical companies.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Experts highlight benefits and offer caveats for first postpartum depression pill
For the first time, the Food and Drug Administration approved a pill taken once daily for 14 days to help women manage the often strong, sometimes overpowering symptoms of postpartum depression.
for a condition that affects an estimated 1 in 8 women in the United States. What will it mean for easing symptoms such as hopelessness, crankiness, and lack of interest in bonding with the baby or, in the case of multiples, babies – and in some cases, thoughts of death or suicide?
A fast-acting option
“We don’t have many oral medications that are fast-acting antidepressants, so this is incredibly exciting,” said Sarah Oreck, MD, a psychiatrist in private practice in Los Angeles who specializes in reproductive psychiatry. The rapid response is likely because the medication targets the hormonal mechanism underlying postpartum depression, she added.
Zuranolone (Zurzuvae, Biogen/Sage) is different from most other antidepressants – it is designed to be taken for a shorter period. Also, Because zuranolone is a pill, it is more convenient to take than the other FDA-approved treatment, the IV infusion brexanolone (Zulresso, Sage).
“It’s obviously game changing to have something in pill form. The infusion has to be done at an infusion center to monitor people for any complications,” said Kimberly Yonkers, MD, a psychiatrist specializing in women’s health, a Distinguished Life Fellow of the American Psychiatric Association (APA), and the Katz Family Chair of Psychiatry at the University of Massachusetts Chan Medical School/UMass Memorial Medical Center in Worcester.
Women may experience improvement in postpartum depression in as soon as 3 days after starting the medication. In contrast, “typical antidepressants can take up to 2 weeks before patients notice a difference and 4 to 8 weeks to see a full response. A fast-acting pill that can be taken orally could be an ideal option for the 15% to 20% of women who experience postpartum depression,” said Priya Gopalan, MD, a psychiatrist with UPMC Western Psychiatric Hospital and Magee-Womens Hospital in Pittsburgh.
The medical community, and reproductive psychiatrists in particular, has always suspected differences in the biological underpinnings of postpartum depression and major depressive disorder, Dr. Oreck said. “We know that postpartum depression looks different from major depressive disorder and that hormonal shifts during pregnancy and postpartum are a huge risk factor for postpartum depression,” she said.
Although selective serotonin reuptake inhibitors (SSRIs) are helpful and currently the standard of care for treating moderate to severe postpartum depression in combination with therapy, Dr. Oreck added, early studies suggest that zuranolone may work faster and potentially be more effective than SSRIs in treating the condition.
Zuranolone is a version of a naturally occurring hormone called allopregnanolone, a metabolite of progesterone. Concentrations of allopregnanolone rise dramatically during pregnancy and then drop precipitously after childbirth. Zuranolone works through modulating GABA-A, a neurotransmitter implicated in the development of depression.
“It is encouraging that postpartum individuals may now have more options to manage a debilitating condition that affects them and their families,” said Christopher Zahn, MD, interim CEO and chief of clinical practice and health equity and quality for the American College of Obstetricians and Gynecologists (ACOG).
ACOG recommends women be screened for depression at least three times – during early pregnancy, later in pregnancy, and again after delivery. A decision to start this or any other medicine should be individualized and based on shared decision-making between a patient and doctor, Dr. Zahn added.
The cost of zuranolone is not yet known. Dr. Yonkers said cost of the infusion can serve as a cautionary tale for the manufacturer. Some reports put the infusion cost at $34,000. “Cost is going to be an important component to this. The previous intervention was priced so high that it was not affordable to many people and it was difficult to access.”
Beyond ‘baby blues’
The APA has changed the name from “postpartum depression” to “peripartum depression” because evidence suggests feelings and symptoms also can start late in pregnancy. “It means you don’t have to wait until somebody delivers to screen for depression. We have to recognize that depression can occur during pregnancy,” Dr. Yonkers said. “In fact it is not uncommon during the third trimester.”
No matter when it starts, the condition can be “very serious,” particularly if the person already experiences depression, including bipolar disorder, Dr. Yonkers added.
Postpartum depression “is more than just ‘baby blues.’ It is a potentially debilitating illness that causes feelings of intense sadness and worthlessness, making it difficult to care for and bond with your newborn,” Dr. Gopalan said.
Can be a medical emergency
Severe postpartum depression requires immediate attention and treatment.
“One of the things we have to be cautious about is for people with previous predisposition to hurt themselves,” Dr. Yonkers said. “It is therefore important to consider somebody’s medical and behavioral health history as well.
“For an individual with recurring depression or severe episodes of depression, this may not be sufficient, because they are just going to get these 14 days of therapy,” Dr. Yonkers said. “They may need ongoing antidepressants.
“It may not be the right pill for everybody,” Dr. Yonkers added. She recommended everyone be followed closely during and after treatment “to make sure they are responding and to monitor for relapse.”
The science that led to approval
The clinical trials showed early response in patients with severe postpartum depression. Researchers conducted two studies of women who developed a major depressive episode in the third trimester of pregnancy or within 4 weeks of delivery. They found women who took zuranolone once in the evening for 14 days “showed significantly more improvement in their symptoms compared to those in the placebo group.”
The antidepressant effect lasted at least 4 weeks after stopping the medication.
Drowsiness, dizziness, diarrhea, fatigue, nasopharyngitis, and urinary tract infection were the most common side effects. The label has a boxed warning noting that the medication can affect a person’s ability to drive and perform other potentially hazardous activities. Use of zuranolone may also cause suicidal thoughts and behavior, according to an FDA news release announcing the approval.
The start of more help for mothers?
Zuranolone is not a cure-all. As with most psychiatric prescriptions, the medication likely will work best in conjunction with behavioral health treatments such as psychotherapy, use of other medications, behavioral management, support groups, and self-care tools such as meditation, exercise, and yoga, Dr. Gopalan said.
Dr. Oreck said she hopes this first pill approval will lead to more discoveries. “I hope this is the beginning of more innovation and development of novel treatments that can target women’s mental health issues specifically – female reproductive hormones impact mental health in unique ways and it’s exciting to finally see research and development dollars dedicated to them,” she said. “The FDA approval of this pill provides the potential to improve the lives of millions of Americans suffering from postpartum depression.”
Dr. Oreck, Dr. Yonkers, Dr. Gopalan, and Dr. Zahn have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
For the first time, the Food and Drug Administration approved a pill taken once daily for 14 days to help women manage the often strong, sometimes overpowering symptoms of postpartum depression.
for a condition that affects an estimated 1 in 8 women in the United States. What will it mean for easing symptoms such as hopelessness, crankiness, and lack of interest in bonding with the baby or, in the case of multiples, babies – and in some cases, thoughts of death or suicide?
A fast-acting option
“We don’t have many oral medications that are fast-acting antidepressants, so this is incredibly exciting,” said Sarah Oreck, MD, a psychiatrist in private practice in Los Angeles who specializes in reproductive psychiatry. The rapid response is likely because the medication targets the hormonal mechanism underlying postpartum depression, she added.
Zuranolone (Zurzuvae, Biogen/Sage) is different from most other antidepressants – it is designed to be taken for a shorter period. Also, Because zuranolone is a pill, it is more convenient to take than the other FDA-approved treatment, the IV infusion brexanolone (Zulresso, Sage).
“It’s obviously game changing to have something in pill form. The infusion has to be done at an infusion center to monitor people for any complications,” said Kimberly Yonkers, MD, a psychiatrist specializing in women’s health, a Distinguished Life Fellow of the American Psychiatric Association (APA), and the Katz Family Chair of Psychiatry at the University of Massachusetts Chan Medical School/UMass Memorial Medical Center in Worcester.
Women may experience improvement in postpartum depression in as soon as 3 days after starting the medication. In contrast, “typical antidepressants can take up to 2 weeks before patients notice a difference and 4 to 8 weeks to see a full response. A fast-acting pill that can be taken orally could be an ideal option for the 15% to 20% of women who experience postpartum depression,” said Priya Gopalan, MD, a psychiatrist with UPMC Western Psychiatric Hospital and Magee-Womens Hospital in Pittsburgh.
The medical community, and reproductive psychiatrists in particular, has always suspected differences in the biological underpinnings of postpartum depression and major depressive disorder, Dr. Oreck said. “We know that postpartum depression looks different from major depressive disorder and that hormonal shifts during pregnancy and postpartum are a huge risk factor for postpartum depression,” she said.
Although selective serotonin reuptake inhibitors (SSRIs) are helpful and currently the standard of care for treating moderate to severe postpartum depression in combination with therapy, Dr. Oreck added, early studies suggest that zuranolone may work faster and potentially be more effective than SSRIs in treating the condition.
Zuranolone is a version of a naturally occurring hormone called allopregnanolone, a metabolite of progesterone. Concentrations of allopregnanolone rise dramatically during pregnancy and then drop precipitously after childbirth. Zuranolone works through modulating GABA-A, a neurotransmitter implicated in the development of depression.
“It is encouraging that postpartum individuals may now have more options to manage a debilitating condition that affects them and their families,” said Christopher Zahn, MD, interim CEO and chief of clinical practice and health equity and quality for the American College of Obstetricians and Gynecologists (ACOG).
ACOG recommends women be screened for depression at least three times – during early pregnancy, later in pregnancy, and again after delivery. A decision to start this or any other medicine should be individualized and based on shared decision-making between a patient and doctor, Dr. Zahn added.
The cost of zuranolone is not yet known. Dr. Yonkers said cost of the infusion can serve as a cautionary tale for the manufacturer. Some reports put the infusion cost at $34,000. “Cost is going to be an important component to this. The previous intervention was priced so high that it was not affordable to many people and it was difficult to access.”
Beyond ‘baby blues’
The APA has changed the name from “postpartum depression” to “peripartum depression” because evidence suggests feelings and symptoms also can start late in pregnancy. “It means you don’t have to wait until somebody delivers to screen for depression. We have to recognize that depression can occur during pregnancy,” Dr. Yonkers said. “In fact it is not uncommon during the third trimester.”
No matter when it starts, the condition can be “very serious,” particularly if the person already experiences depression, including bipolar disorder, Dr. Yonkers added.
Postpartum depression “is more than just ‘baby blues.’ It is a potentially debilitating illness that causes feelings of intense sadness and worthlessness, making it difficult to care for and bond with your newborn,” Dr. Gopalan said.
Can be a medical emergency
Severe postpartum depression requires immediate attention and treatment.
“One of the things we have to be cautious about is for people with previous predisposition to hurt themselves,” Dr. Yonkers said. “It is therefore important to consider somebody’s medical and behavioral health history as well.
“For an individual with recurring depression or severe episodes of depression, this may not be sufficient, because they are just going to get these 14 days of therapy,” Dr. Yonkers said. “They may need ongoing antidepressants.
“It may not be the right pill for everybody,” Dr. Yonkers added. She recommended everyone be followed closely during and after treatment “to make sure they are responding and to monitor for relapse.”
The science that led to approval
The clinical trials showed early response in patients with severe postpartum depression. Researchers conducted two studies of women who developed a major depressive episode in the third trimester of pregnancy or within 4 weeks of delivery. They found women who took zuranolone once in the evening for 14 days “showed significantly more improvement in their symptoms compared to those in the placebo group.”
The antidepressant effect lasted at least 4 weeks after stopping the medication.
Drowsiness, dizziness, diarrhea, fatigue, nasopharyngitis, and urinary tract infection were the most common side effects. The label has a boxed warning noting that the medication can affect a person’s ability to drive and perform other potentially hazardous activities. Use of zuranolone may also cause suicidal thoughts and behavior, according to an FDA news release announcing the approval.
The start of more help for mothers?
Zuranolone is not a cure-all. As with most psychiatric prescriptions, the medication likely will work best in conjunction with behavioral health treatments such as psychotherapy, use of other medications, behavioral management, support groups, and self-care tools such as meditation, exercise, and yoga, Dr. Gopalan said.
Dr. Oreck said she hopes this first pill approval will lead to more discoveries. “I hope this is the beginning of more innovation and development of novel treatments that can target women’s mental health issues specifically – female reproductive hormones impact mental health in unique ways and it’s exciting to finally see research and development dollars dedicated to them,” she said. “The FDA approval of this pill provides the potential to improve the lives of millions of Americans suffering from postpartum depression.”
Dr. Oreck, Dr. Yonkers, Dr. Gopalan, and Dr. Zahn have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
For the first time, the Food and Drug Administration approved a pill taken once daily for 14 days to help women manage the often strong, sometimes overpowering symptoms of postpartum depression.
for a condition that affects an estimated 1 in 8 women in the United States. What will it mean for easing symptoms such as hopelessness, crankiness, and lack of interest in bonding with the baby or, in the case of multiples, babies – and in some cases, thoughts of death or suicide?
A fast-acting option
“We don’t have many oral medications that are fast-acting antidepressants, so this is incredibly exciting,” said Sarah Oreck, MD, a psychiatrist in private practice in Los Angeles who specializes in reproductive psychiatry. The rapid response is likely because the medication targets the hormonal mechanism underlying postpartum depression, she added.
Zuranolone (Zurzuvae, Biogen/Sage) is different from most other antidepressants – it is designed to be taken for a shorter period. Also, Because zuranolone is a pill, it is more convenient to take than the other FDA-approved treatment, the IV infusion brexanolone (Zulresso, Sage).
“It’s obviously game changing to have something in pill form. The infusion has to be done at an infusion center to monitor people for any complications,” said Kimberly Yonkers, MD, a psychiatrist specializing in women’s health, a Distinguished Life Fellow of the American Psychiatric Association (APA), and the Katz Family Chair of Psychiatry at the University of Massachusetts Chan Medical School/UMass Memorial Medical Center in Worcester.
Women may experience improvement in postpartum depression in as soon as 3 days after starting the medication. In contrast, “typical antidepressants can take up to 2 weeks before patients notice a difference and 4 to 8 weeks to see a full response. A fast-acting pill that can be taken orally could be an ideal option for the 15% to 20% of women who experience postpartum depression,” said Priya Gopalan, MD, a psychiatrist with UPMC Western Psychiatric Hospital and Magee-Womens Hospital in Pittsburgh.
The medical community, and reproductive psychiatrists in particular, has always suspected differences in the biological underpinnings of postpartum depression and major depressive disorder, Dr. Oreck said. “We know that postpartum depression looks different from major depressive disorder and that hormonal shifts during pregnancy and postpartum are a huge risk factor for postpartum depression,” she said.
Although selective serotonin reuptake inhibitors (SSRIs) are helpful and currently the standard of care for treating moderate to severe postpartum depression in combination with therapy, Dr. Oreck added, early studies suggest that zuranolone may work faster and potentially be more effective than SSRIs in treating the condition.
Zuranolone is a version of a naturally occurring hormone called allopregnanolone, a metabolite of progesterone. Concentrations of allopregnanolone rise dramatically during pregnancy and then drop precipitously after childbirth. Zuranolone works through modulating GABA-A, a neurotransmitter implicated in the development of depression.
“It is encouraging that postpartum individuals may now have more options to manage a debilitating condition that affects them and their families,” said Christopher Zahn, MD, interim CEO and chief of clinical practice and health equity and quality for the American College of Obstetricians and Gynecologists (ACOG).
ACOG recommends women be screened for depression at least three times – during early pregnancy, later in pregnancy, and again after delivery. A decision to start this or any other medicine should be individualized and based on shared decision-making between a patient and doctor, Dr. Zahn added.
The cost of zuranolone is not yet known. Dr. Yonkers said cost of the infusion can serve as a cautionary tale for the manufacturer. Some reports put the infusion cost at $34,000. “Cost is going to be an important component to this. The previous intervention was priced so high that it was not affordable to many people and it was difficult to access.”
Beyond ‘baby blues’
The APA has changed the name from “postpartum depression” to “peripartum depression” because evidence suggests feelings and symptoms also can start late in pregnancy. “It means you don’t have to wait until somebody delivers to screen for depression. We have to recognize that depression can occur during pregnancy,” Dr. Yonkers said. “In fact it is not uncommon during the third trimester.”
No matter when it starts, the condition can be “very serious,” particularly if the person already experiences depression, including bipolar disorder, Dr. Yonkers added.
Postpartum depression “is more than just ‘baby blues.’ It is a potentially debilitating illness that causes feelings of intense sadness and worthlessness, making it difficult to care for and bond with your newborn,” Dr. Gopalan said.
Can be a medical emergency
Severe postpartum depression requires immediate attention and treatment.
“One of the things we have to be cautious about is for people with previous predisposition to hurt themselves,” Dr. Yonkers said. “It is therefore important to consider somebody’s medical and behavioral health history as well.
“For an individual with recurring depression or severe episodes of depression, this may not be sufficient, because they are just going to get these 14 days of therapy,” Dr. Yonkers said. “They may need ongoing antidepressants.
“It may not be the right pill for everybody,” Dr. Yonkers added. She recommended everyone be followed closely during and after treatment “to make sure they are responding and to monitor for relapse.”
The science that led to approval
The clinical trials showed early response in patients with severe postpartum depression. Researchers conducted two studies of women who developed a major depressive episode in the third trimester of pregnancy or within 4 weeks of delivery. They found women who took zuranolone once in the evening for 14 days “showed significantly more improvement in their symptoms compared to those in the placebo group.”
The antidepressant effect lasted at least 4 weeks after stopping the medication.
Drowsiness, dizziness, diarrhea, fatigue, nasopharyngitis, and urinary tract infection were the most common side effects. The label has a boxed warning noting that the medication can affect a person’s ability to drive and perform other potentially hazardous activities. Use of zuranolone may also cause suicidal thoughts and behavior, according to an FDA news release announcing the approval.
The start of more help for mothers?
Zuranolone is not a cure-all. As with most psychiatric prescriptions, the medication likely will work best in conjunction with behavioral health treatments such as psychotherapy, use of other medications, behavioral management, support groups, and self-care tools such as meditation, exercise, and yoga, Dr. Gopalan said.
Dr. Oreck said she hopes this first pill approval will lead to more discoveries. “I hope this is the beginning of more innovation and development of novel treatments that can target women’s mental health issues specifically – female reproductive hormones impact mental health in unique ways and it’s exciting to finally see research and development dollars dedicated to them,” she said. “The FDA approval of this pill provides the potential to improve the lives of millions of Americans suffering from postpartum depression.”
Dr. Oreck, Dr. Yonkers, Dr. Gopalan, and Dr. Zahn have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
‘Triple G’ agonist hits new weight loss heights
A novel triple agonist to receptors for three nutrient-stimulated hormones led to weight loss as high as 24% among people with overweight or obesity but who did not have type 2 diabetes when used at the highest tested dose for 48 weeks. The results are from a phase 2 study of retatrutide that was published in The New England Journal of Medicine (2023 Aug 10. doi: 10.1056/NEJMoa2301972).
This level of weight loss is “unprecedented” for a medication administered for 48 weeks, Mary-Elizabeth Patti, MD, said in an editorial that accompanied the report.
The findings “offer further optimism ... that effective pharmacologic management of obesity and related disorders is possible,” wrote Dr. Patti, a principal investigator at the Joslin Diabetes Center in Boston.
The study randomly assigned 338 adults with obesity or overweight – a body mass index (BMI) of ≥ 27 kg/m2 – and at least one weight-related complication to receive either weekly subcutaneous injections of retatrutide in any of six dose regimens or placebo over 48 weeks. The primary outcome was weight change from baseline after 24 weeks.
The highest dose of retatrutide safely produced an average 17.5% drop from baseline weight, compared with an average 1.6% reduction in the placebo group, after 24 weeks, a significant difference.
After 48 weeks, the highest retatrutide dose safely cut baseline weight by an average of 24.2%, compared with an average 2.1% drop among placebo control patients, Ania M. Jastreboff, MD, PhD, and her coauthors wrote in their report. Weight loss levels after 24 and 48 weeks of retatrutide treatment followed a clear dose-response pattern.
Weight losses never before seen
“I have never seen weight loss at this level” after nearly 1 year of treatment, Dr. Jastreboff said when she discussed these findings in a press conference at the annual scientific sessions of the American Diabetes Association in San Diego in late June.
A separate presentation at the ADA meeting documented unprecedented weight loss levels in a study of 281 people with obesity or overweight and type 2 diabetes.
“No other medication has shown an average 17% reduction from baseline bodyweight after 36 weeks in people with type 2 diabetes,” said Julio Rosenstock, MD, director of the Dallas Diabetes Research Center at Medical City, Texas, who formally presented the results from the study of retatrutide in people with type 2 diabetes at the ADA meeting.
The mechanism behind retatrutide’s potent weight-loss effect seems likely tied to its action on three human receptors that naturally respond to three nutrient-stimulated hormones that control appetite, metabolism, fat mobilization, and related functions.
The three hormones that the retatrutide molecule simultaneously mimics are glucagon-like peptide-1 (GLP-1), such as agents in the class of GLP-1 agonists that includes liraglutide (Victoza/Saxenda) and semaglutide (Ozempic/Wegovy); the glucose-dependent insulinotropic polypeptide (GIP), the receptor that is also activated by tirzepatide (Mounjaro), a dual-incretin receptor agonist that mimics both GLP-1 and GIP; and glucagon. Survodutide is a dual GLP-1 and glucagon receptor agonist in phase 2 development.
Retatrutide is currently unique among agents with reported clinical results by having agonist effects on the receptors for all three of these hormones, a property that led Dr. Patti to call retatrutide a “triple G” hormone-receptor agonist in her editorial.
Triple agonist has added effect on liver fat clearance
The glucagon-receptor agonism appears to give retatrutide added effects beyond those of the GLP-1 agonists or GLP-1/GIP dual agonists that are increasingly used in U.S. practice.
A prespecified subgroup analysis of the no diabetes/Jastreboff study (but that was not included in the NEJM report) showed that at both 8-mg and 12-mg weekly doses, 24 weeks of retatrutide produced complete resolution of excess liver fat (hepatic steatosis) in about 80% of the people eligible for the analysis (those whose liver volume was at least 10% fat at study entry).
That percentage increased to about 90% of people receiving these doses after 48 weeks, Lee M. Kaplan, MD, reported during a separate presentation at the ADA meeting.
“When you add glucagon activity, liver-fat clearance goes up tremendously,” observed Dr. Kaplan, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital in Boston.
The average age of the participants in the new study of the use of retatrutide for those with obesity/overweight but not diabetes was 48 years. By design, 52% were men. (The study sought to enroll roughly equal numbers of men and women.) Average BMI at study entry was 37 kg/m2.
Treatment with retatrutide was also significantly associated with improvements in several cardiometabolic measures in exploratory analyses, including systolic and diastolic blood pressure, A1c, fasting glucose, insulin, and some (but not all) lipids, Dr. Jastreboff, director of the Yale Obesity Research Center of Yale University in New Haven, Conn., and her coauthors reported in the NEJM article.
The safety profile of retatrutide was consistent with reported phase 1 findings for the agent among people with type 2 diabetes and resembled the safety profiles of other agents based on GLP-1 or GIP–GLP-1 mimicry for the treatment of type 2 diabetes or obesity.
The most frequently reported adverse events from retatrutide were transient, mostly mild to moderate gastrointestinal events. They occurred primarily during dose escalation. Discontinuation of retatrutide or placebo because of adverse events occurred in 6% to 16% of the participants who received retatrutide and in none of the participants who received placebo.
Lilly, the company developing retatrutide, previously announced the launch of four phase 3 trials to gather further data on retatrutide for use in a marketing-approval application to the Food and Drug Administration.
The four trials – TRIUMPH-1, TRIUMPH-2, TRIUMPH-3, and TRIUMPH-4 – are evaluating the safety and efficacy of retatrutide for chronic weight management for those with obesity or overweight, including those who also have obstructive sleep apnea, knee osteoarthritis, type 2 diabetes, or cardiovascular disease.
The study was sponsored by Lilly, the company developing retatrutide. Dr. Patti has been a consultant to AstraZeneca, Dexcom, Hanmi, and MBX. She has received funding from Dexcom and has been a monitor for a trial funded by Fractyl. Dr. Jastreboff, Dr. Kaplan, and Dr. Rosenstock have reported financial relationships with Lilly as well as other companies.
A version of this article first appeared on Medscape.com.
A novel triple agonist to receptors for three nutrient-stimulated hormones led to weight loss as high as 24% among people with overweight or obesity but who did not have type 2 diabetes when used at the highest tested dose for 48 weeks. The results are from a phase 2 study of retatrutide that was published in The New England Journal of Medicine (2023 Aug 10. doi: 10.1056/NEJMoa2301972).
This level of weight loss is “unprecedented” for a medication administered for 48 weeks, Mary-Elizabeth Patti, MD, said in an editorial that accompanied the report.
The findings “offer further optimism ... that effective pharmacologic management of obesity and related disorders is possible,” wrote Dr. Patti, a principal investigator at the Joslin Diabetes Center in Boston.
The study randomly assigned 338 adults with obesity or overweight – a body mass index (BMI) of ≥ 27 kg/m2 – and at least one weight-related complication to receive either weekly subcutaneous injections of retatrutide in any of six dose regimens or placebo over 48 weeks. The primary outcome was weight change from baseline after 24 weeks.
The highest dose of retatrutide safely produced an average 17.5% drop from baseline weight, compared with an average 1.6% reduction in the placebo group, after 24 weeks, a significant difference.
After 48 weeks, the highest retatrutide dose safely cut baseline weight by an average of 24.2%, compared with an average 2.1% drop among placebo control patients, Ania M. Jastreboff, MD, PhD, and her coauthors wrote in their report. Weight loss levels after 24 and 48 weeks of retatrutide treatment followed a clear dose-response pattern.
Weight losses never before seen
“I have never seen weight loss at this level” after nearly 1 year of treatment, Dr. Jastreboff said when she discussed these findings in a press conference at the annual scientific sessions of the American Diabetes Association in San Diego in late June.
A separate presentation at the ADA meeting documented unprecedented weight loss levels in a study of 281 people with obesity or overweight and type 2 diabetes.
“No other medication has shown an average 17% reduction from baseline bodyweight after 36 weeks in people with type 2 diabetes,” said Julio Rosenstock, MD, director of the Dallas Diabetes Research Center at Medical City, Texas, who formally presented the results from the study of retatrutide in people with type 2 diabetes at the ADA meeting.
The mechanism behind retatrutide’s potent weight-loss effect seems likely tied to its action on three human receptors that naturally respond to three nutrient-stimulated hormones that control appetite, metabolism, fat mobilization, and related functions.
The three hormones that the retatrutide molecule simultaneously mimics are glucagon-like peptide-1 (GLP-1), such as agents in the class of GLP-1 agonists that includes liraglutide (Victoza/Saxenda) and semaglutide (Ozempic/Wegovy); the glucose-dependent insulinotropic polypeptide (GIP), the receptor that is also activated by tirzepatide (Mounjaro), a dual-incretin receptor agonist that mimics both GLP-1 and GIP; and glucagon. Survodutide is a dual GLP-1 and glucagon receptor agonist in phase 2 development.
Retatrutide is currently unique among agents with reported clinical results by having agonist effects on the receptors for all three of these hormones, a property that led Dr. Patti to call retatrutide a “triple G” hormone-receptor agonist in her editorial.
Triple agonist has added effect on liver fat clearance
The glucagon-receptor agonism appears to give retatrutide added effects beyond those of the GLP-1 agonists or GLP-1/GIP dual agonists that are increasingly used in U.S. practice.
A prespecified subgroup analysis of the no diabetes/Jastreboff study (but that was not included in the NEJM report) showed that at both 8-mg and 12-mg weekly doses, 24 weeks of retatrutide produced complete resolution of excess liver fat (hepatic steatosis) in about 80% of the people eligible for the analysis (those whose liver volume was at least 10% fat at study entry).
That percentage increased to about 90% of people receiving these doses after 48 weeks, Lee M. Kaplan, MD, reported during a separate presentation at the ADA meeting.
“When you add glucagon activity, liver-fat clearance goes up tremendously,” observed Dr. Kaplan, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital in Boston.
The average age of the participants in the new study of the use of retatrutide for those with obesity/overweight but not diabetes was 48 years. By design, 52% were men. (The study sought to enroll roughly equal numbers of men and women.) Average BMI at study entry was 37 kg/m2.
Treatment with retatrutide was also significantly associated with improvements in several cardiometabolic measures in exploratory analyses, including systolic and diastolic blood pressure, A1c, fasting glucose, insulin, and some (but not all) lipids, Dr. Jastreboff, director of the Yale Obesity Research Center of Yale University in New Haven, Conn., and her coauthors reported in the NEJM article.
The safety profile of retatrutide was consistent with reported phase 1 findings for the agent among people with type 2 diabetes and resembled the safety profiles of other agents based on GLP-1 or GIP–GLP-1 mimicry for the treatment of type 2 diabetes or obesity.
The most frequently reported adverse events from retatrutide were transient, mostly mild to moderate gastrointestinal events. They occurred primarily during dose escalation. Discontinuation of retatrutide or placebo because of adverse events occurred in 6% to 16% of the participants who received retatrutide and in none of the participants who received placebo.
Lilly, the company developing retatrutide, previously announced the launch of four phase 3 trials to gather further data on retatrutide for use in a marketing-approval application to the Food and Drug Administration.
The four trials – TRIUMPH-1, TRIUMPH-2, TRIUMPH-3, and TRIUMPH-4 – are evaluating the safety and efficacy of retatrutide for chronic weight management for those with obesity or overweight, including those who also have obstructive sleep apnea, knee osteoarthritis, type 2 diabetes, or cardiovascular disease.
The study was sponsored by Lilly, the company developing retatrutide. Dr. Patti has been a consultant to AstraZeneca, Dexcom, Hanmi, and MBX. She has received funding from Dexcom and has been a monitor for a trial funded by Fractyl. Dr. Jastreboff, Dr. Kaplan, and Dr. Rosenstock have reported financial relationships with Lilly as well as other companies.
A version of this article first appeared on Medscape.com.
A novel triple agonist to receptors for three nutrient-stimulated hormones led to weight loss as high as 24% among people with overweight or obesity but who did not have type 2 diabetes when used at the highest tested dose for 48 weeks. The results are from a phase 2 study of retatrutide that was published in The New England Journal of Medicine (2023 Aug 10. doi: 10.1056/NEJMoa2301972).
This level of weight loss is “unprecedented” for a medication administered for 48 weeks, Mary-Elizabeth Patti, MD, said in an editorial that accompanied the report.
The findings “offer further optimism ... that effective pharmacologic management of obesity and related disorders is possible,” wrote Dr. Patti, a principal investigator at the Joslin Diabetes Center in Boston.
The study randomly assigned 338 adults with obesity or overweight – a body mass index (BMI) of ≥ 27 kg/m2 – and at least one weight-related complication to receive either weekly subcutaneous injections of retatrutide in any of six dose regimens or placebo over 48 weeks. The primary outcome was weight change from baseline after 24 weeks.
The highest dose of retatrutide safely produced an average 17.5% drop from baseline weight, compared with an average 1.6% reduction in the placebo group, after 24 weeks, a significant difference.
After 48 weeks, the highest retatrutide dose safely cut baseline weight by an average of 24.2%, compared with an average 2.1% drop among placebo control patients, Ania M. Jastreboff, MD, PhD, and her coauthors wrote in their report. Weight loss levels after 24 and 48 weeks of retatrutide treatment followed a clear dose-response pattern.
Weight losses never before seen
“I have never seen weight loss at this level” after nearly 1 year of treatment, Dr. Jastreboff said when she discussed these findings in a press conference at the annual scientific sessions of the American Diabetes Association in San Diego in late June.
A separate presentation at the ADA meeting documented unprecedented weight loss levels in a study of 281 people with obesity or overweight and type 2 diabetes.
“No other medication has shown an average 17% reduction from baseline bodyweight after 36 weeks in people with type 2 diabetes,” said Julio Rosenstock, MD, director of the Dallas Diabetes Research Center at Medical City, Texas, who formally presented the results from the study of retatrutide in people with type 2 diabetes at the ADA meeting.
The mechanism behind retatrutide’s potent weight-loss effect seems likely tied to its action on three human receptors that naturally respond to three nutrient-stimulated hormones that control appetite, metabolism, fat mobilization, and related functions.
The three hormones that the retatrutide molecule simultaneously mimics are glucagon-like peptide-1 (GLP-1), such as agents in the class of GLP-1 agonists that includes liraglutide (Victoza/Saxenda) and semaglutide (Ozempic/Wegovy); the glucose-dependent insulinotropic polypeptide (GIP), the receptor that is also activated by tirzepatide (Mounjaro), a dual-incretin receptor agonist that mimics both GLP-1 and GIP; and glucagon. Survodutide is a dual GLP-1 and glucagon receptor agonist in phase 2 development.
Retatrutide is currently unique among agents with reported clinical results by having agonist effects on the receptors for all three of these hormones, a property that led Dr. Patti to call retatrutide a “triple G” hormone-receptor agonist in her editorial.
Triple agonist has added effect on liver fat clearance
The glucagon-receptor agonism appears to give retatrutide added effects beyond those of the GLP-1 agonists or GLP-1/GIP dual agonists that are increasingly used in U.S. practice.
A prespecified subgroup analysis of the no diabetes/Jastreboff study (but that was not included in the NEJM report) showed that at both 8-mg and 12-mg weekly doses, 24 weeks of retatrutide produced complete resolution of excess liver fat (hepatic steatosis) in about 80% of the people eligible for the analysis (those whose liver volume was at least 10% fat at study entry).
That percentage increased to about 90% of people receiving these doses after 48 weeks, Lee M. Kaplan, MD, reported during a separate presentation at the ADA meeting.
“When you add glucagon activity, liver-fat clearance goes up tremendously,” observed Dr. Kaplan, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital in Boston.
The average age of the participants in the new study of the use of retatrutide for those with obesity/overweight but not diabetes was 48 years. By design, 52% were men. (The study sought to enroll roughly equal numbers of men and women.) Average BMI at study entry was 37 kg/m2.
Treatment with retatrutide was also significantly associated with improvements in several cardiometabolic measures in exploratory analyses, including systolic and diastolic blood pressure, A1c, fasting glucose, insulin, and some (but not all) lipids, Dr. Jastreboff, director of the Yale Obesity Research Center of Yale University in New Haven, Conn., and her coauthors reported in the NEJM article.
The safety profile of retatrutide was consistent with reported phase 1 findings for the agent among people with type 2 diabetes and resembled the safety profiles of other agents based on GLP-1 or GIP–GLP-1 mimicry for the treatment of type 2 diabetes or obesity.
The most frequently reported adverse events from retatrutide were transient, mostly mild to moderate gastrointestinal events. They occurred primarily during dose escalation. Discontinuation of retatrutide or placebo because of adverse events occurred in 6% to 16% of the participants who received retatrutide and in none of the participants who received placebo.
Lilly, the company developing retatrutide, previously announced the launch of four phase 3 trials to gather further data on retatrutide for use in a marketing-approval application to the Food and Drug Administration.
The four trials – TRIUMPH-1, TRIUMPH-2, TRIUMPH-3, and TRIUMPH-4 – are evaluating the safety and efficacy of retatrutide for chronic weight management for those with obesity or overweight, including those who also have obstructive sleep apnea, knee osteoarthritis, type 2 diabetes, or cardiovascular disease.
The study was sponsored by Lilly, the company developing retatrutide. Dr. Patti has been a consultant to AstraZeneca, Dexcom, Hanmi, and MBX. She has received funding from Dexcom and has been a monitor for a trial funded by Fractyl. Dr. Jastreboff, Dr. Kaplan, and Dr. Rosenstock have reported financial relationships with Lilly as well as other companies.
A version of this article first appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Medical treatment for appendicitis effective long-term
TOPLINE:
Most patients who receive antibiotics rather than surgical treatment for appendicitis have successful long-term outcomes, but some may require surgery up to 20 years later.
METHODOLOGY:
- Follow-up on 292 patients involved in two randomized controlled trials conducted in the 1990s by the Swedish National Patient Registry
- Both trials divided patients into two groups: those who underwent appendectomy and those who received antibiotic treatment for appendicitis.
- Researchers looked at rates of recurrent appendicitis that required surgery later in life.
TAKEAWAY:
- 29% of patients in the nonoperative group who were discharged successfully during the initial study eventually underwent surgery.
- Some patients who initially received antibiotics required surgery up to 20 years later.
- 9.5% of patients who didn’t undergo surgery went to a surgical outpatient clinic for abdominal pain, compared with 0.01% of those who had surgery.
IN PRACTICE:
“More than half of the patients treated nonoperatively did not experience recurrence and avoided surgery over approximately 2 decades. There is no evidence for long-term risks of nonoperative management other than that of recurrence of appendicitis,” the authors report.
SOURCE:
Simon Eaton, PhD, of UCL Great Ormond Street Institute of Child Health in London, was the corresponding author of the study, published online in JAMA Surgery. The study was funded by the NIHR Biomedical Research Centre at Great Ormond Street Hospital and the Swedish Research Council.
LIMITATIONS:
The data were retrospective, so the researchers could not track how patients’ circumstances and characteristics changed over time. Most patients were male, and the researchers lacked histopathology results for patients for whom nonsurgical treatment succeeded initially but who later required appendectomy. They also relied on diagnostic standards used in the 1990s, when the initial studies were performed; these were less sophisticated and accurate than recent standards.
DISCLOSURES:
Coauthor Jan Svensson, MD, PhD, reported receiving grants from the Lovisa Foundation during the conduct of the study. No other disclosures were reported.
A version of this article first appeared on Medscape.com.
TOPLINE:
Most patients who receive antibiotics rather than surgical treatment for appendicitis have successful long-term outcomes, but some may require surgery up to 20 years later.
METHODOLOGY:
- Follow-up on 292 patients involved in two randomized controlled trials conducted in the 1990s by the Swedish National Patient Registry
- Both trials divided patients into two groups: those who underwent appendectomy and those who received antibiotic treatment for appendicitis.
- Researchers looked at rates of recurrent appendicitis that required surgery later in life.
TAKEAWAY:
- 29% of patients in the nonoperative group who were discharged successfully during the initial study eventually underwent surgery.
- Some patients who initially received antibiotics required surgery up to 20 years later.
- 9.5% of patients who didn’t undergo surgery went to a surgical outpatient clinic for abdominal pain, compared with 0.01% of those who had surgery.
IN PRACTICE:
“More than half of the patients treated nonoperatively did not experience recurrence and avoided surgery over approximately 2 decades. There is no evidence for long-term risks of nonoperative management other than that of recurrence of appendicitis,” the authors report.
SOURCE:
Simon Eaton, PhD, of UCL Great Ormond Street Institute of Child Health in London, was the corresponding author of the study, published online in JAMA Surgery. The study was funded by the NIHR Biomedical Research Centre at Great Ormond Street Hospital and the Swedish Research Council.
LIMITATIONS:
The data were retrospective, so the researchers could not track how patients’ circumstances and characteristics changed over time. Most patients were male, and the researchers lacked histopathology results for patients for whom nonsurgical treatment succeeded initially but who later required appendectomy. They also relied on diagnostic standards used in the 1990s, when the initial studies were performed; these were less sophisticated and accurate than recent standards.
DISCLOSURES:
Coauthor Jan Svensson, MD, PhD, reported receiving grants from the Lovisa Foundation during the conduct of the study. No other disclosures were reported.
A version of this article first appeared on Medscape.com.
TOPLINE:
Most patients who receive antibiotics rather than surgical treatment for appendicitis have successful long-term outcomes, but some may require surgery up to 20 years later.
METHODOLOGY:
- Follow-up on 292 patients involved in two randomized controlled trials conducted in the 1990s by the Swedish National Patient Registry
- Both trials divided patients into two groups: those who underwent appendectomy and those who received antibiotic treatment for appendicitis.
- Researchers looked at rates of recurrent appendicitis that required surgery later in life.
TAKEAWAY:
- 29% of patients in the nonoperative group who were discharged successfully during the initial study eventually underwent surgery.
- Some patients who initially received antibiotics required surgery up to 20 years later.
- 9.5% of patients who didn’t undergo surgery went to a surgical outpatient clinic for abdominal pain, compared with 0.01% of those who had surgery.
IN PRACTICE:
“More than half of the patients treated nonoperatively did not experience recurrence and avoided surgery over approximately 2 decades. There is no evidence for long-term risks of nonoperative management other than that of recurrence of appendicitis,” the authors report.
SOURCE:
Simon Eaton, PhD, of UCL Great Ormond Street Institute of Child Health in London, was the corresponding author of the study, published online in JAMA Surgery. The study was funded by the NIHR Biomedical Research Centre at Great Ormond Street Hospital and the Swedish Research Council.
LIMITATIONS:
The data were retrospective, so the researchers could not track how patients’ circumstances and characteristics changed over time. Most patients were male, and the researchers lacked histopathology results for patients for whom nonsurgical treatment succeeded initially but who later required appendectomy. They also relied on diagnostic standards used in the 1990s, when the initial studies were performed; these were less sophisticated and accurate than recent standards.
DISCLOSURES:
Coauthor Jan Svensson, MD, PhD, reported receiving grants from the Lovisa Foundation during the conduct of the study. No other disclosures were reported.
A version of this article first appeared on Medscape.com.
For CLL, BTKi combo bests chemoimmunotherapy
The analysis of the open-label FLAIR trial, published in The Lancet Oncology, tracked 771 patients with CLL for a median follow-up of 53 months (interquartile ratio, 41-61 months) and found that median progression-free survival was not reached with ibrutinib/rituximab versus 67 months with FCR (hazard ratio, 0.44, P < .0001).
“This paper is another confirmation to say that Bruton’s tyrosine kinase inhibitors are more powerful than even our strongest chemoimmunotherapy. That’s very reassuring,” said hematologist/oncologist Jan A. Burger, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, in an interview. He did not take part in the analysis but is familiar with its findings.
There are caveats to the study. More patients in the ibrutinib/rituximab arm died of cardiac events, possibly reflecting a known risk of those drugs. And for unclear reasons, there was no difference in overall survival – a secondary endpoint – between the groups. The study authors speculate that this may be because some patients on FCR progressed and turned to effective second-line drugs.
Still, the findings are consistent with the landmark E1912 trial, the authors wrote, and adds “to a body of evidence that suggests that the use of ibrutinib-based regimens should be considered for patients with previously untreated CLL, especially those with IGHV-unmutated CLL.”
The study, partially funded by industry, was led by Peter Hillmen, PhD, of Leeds (England) Cancer Center.
According to Dr. Burger, FCR was the standard treatment for younger, fitter patients with CLL about 10-15 years ago. Then Bruton’s tyrosine kinase inhibitors such as ibrutinib entered the picture. But, as the new report notes, initial studies focused on older patients who weren’t considered fit enough to tolerate FCR.
The new study, like the E1912 trial, aimed to compare ibrutinib-rituximab versus FCR in younger, fitter patients.
From 2014 to 2018, researchers assigned 771 patients (median age, 62 years; IQR 56-67; 73% male; 95% White; 66% with World Health Organization performance status, 0) to FCR (n = 385) or ibrutinib/rituximab (n = 386).
Nearly three-quarters (74%) in the FCR group received six cycles of therapy, and 97% of those in the ibrutinib-rituximab group received six cycles of rituximab. Those in the ibrutinib-rituximab group also received daily doses of ibrutinib. Doses could be modified. The data cutoff was May 24, 2021.
Notably, there was no improvement in overall survival in the ibrutinib/rituximab group: 92.1% of patients lived 4 years versus 93.5% in the FCR group. This contrasts with an improvement in overall survival in the earlier E1912 study in the ibrutinib/rituximab group.
However, the study authors noted that overall survival in the FCR group is higher than in earlier studies, perhaps reflecting the wider availability of targeted therapy. The final study analysis will offer more insight into overall survival.
In an interview, hematologist David A. Bond, MD, of Ohio State University, Columbus, who is familiar with the study findings, said “the lack of an improvement in overall survival could be due to differences in available treatments at relapse, as the FLAIR study was conducted more recently than the prior E1912 study.” He added that “the younger ages in the E1912 study may have led to less risk for cardiovascular events or deaths for the patients treated with ibrutinib in the E1912 study.”
The previous E1912 trial showed a larger effect for ibrutinib/rituximab versus FCR on progression-free survival (HR, 0.37, P < .001 for E1912 and HR, 0.44, P< .0001 for the FLAIR trial). However, the study authors noted that FLAIR trial had older subjects (mean age, 62 vs 56.7 in the E1912 trial.)
As for grade 3 or 4 adverse events, leukopenia was most common in the FCR group (n = 203, 54%), compared with the ibrutinib/rituximab group (n = 55, 14%). Serious adverse events were reported in 205 (53%) of patients in the ibrutinib/rituximab group versus 203 (54%) patients in the FCR group.
All-cause infections, myelodysplastic syndrome, acute myeloid leukemia, Richter’s transformation, and other diagnosed cancers were rare but more common in the FCR group. Deaths from COVID-19 were the same at 3 in each group; 2 of 29 deaths in the FCR group and 3 of 30 deaths in the ibrutinib/rituximab group were considered to be likely linked to treatment.
Sudden unexplained or cardiac deaths were more common in the ibrutinib-rituximab group (n = 8, 2%) vs. the FCR group (n = 2, less than 1%).
Dr. Bond said “one of the takeaways for practicing hematologists from the FLAIR study is that cardiovascular complications and sudden cardiac death are clearly an issue for older patients with hypertension treated with ibrutinib. Patients should be monitored for signs or symptoms of cardiovascular disease and have close management of blood pressure.”
Dr. Burger also noted that cardiac problems are a known risk of ibrutinib. “Fortunately, we have second-generation Bruton’s tyrosine kinase inhibitors that could be chosen for patients when we are worried about side effects.”
He said that chemotherapy remains the preferred – or only – treatment in some parts of the world. And patients may prefer FCR to ibrutinib because of the latter drug’s side effects or a preference for therapy that doesn’t take as long.
The study was funded by Cancer Research UK and Janssen. The study authors reported relationships with companies such as Lilly, Janssen, AbbVie, AstraZeneca, BeiGene, Gilead, and many others. Dr. Burger reports financial support for clinical trials from Pharmacyclics, AstraZeneca, Biogen, and Janssen. Dr. Bond reported no disclosures.
The analysis of the open-label FLAIR trial, published in The Lancet Oncology, tracked 771 patients with CLL for a median follow-up of 53 months (interquartile ratio, 41-61 months) and found that median progression-free survival was not reached with ibrutinib/rituximab versus 67 months with FCR (hazard ratio, 0.44, P < .0001).
“This paper is another confirmation to say that Bruton’s tyrosine kinase inhibitors are more powerful than even our strongest chemoimmunotherapy. That’s very reassuring,” said hematologist/oncologist Jan A. Burger, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, in an interview. He did not take part in the analysis but is familiar with its findings.
There are caveats to the study. More patients in the ibrutinib/rituximab arm died of cardiac events, possibly reflecting a known risk of those drugs. And for unclear reasons, there was no difference in overall survival – a secondary endpoint – between the groups. The study authors speculate that this may be because some patients on FCR progressed and turned to effective second-line drugs.
Still, the findings are consistent with the landmark E1912 trial, the authors wrote, and adds “to a body of evidence that suggests that the use of ibrutinib-based regimens should be considered for patients with previously untreated CLL, especially those with IGHV-unmutated CLL.”
The study, partially funded by industry, was led by Peter Hillmen, PhD, of Leeds (England) Cancer Center.
According to Dr. Burger, FCR was the standard treatment for younger, fitter patients with CLL about 10-15 years ago. Then Bruton’s tyrosine kinase inhibitors such as ibrutinib entered the picture. But, as the new report notes, initial studies focused on older patients who weren’t considered fit enough to tolerate FCR.
The new study, like the E1912 trial, aimed to compare ibrutinib-rituximab versus FCR in younger, fitter patients.
From 2014 to 2018, researchers assigned 771 patients (median age, 62 years; IQR 56-67; 73% male; 95% White; 66% with World Health Organization performance status, 0) to FCR (n = 385) or ibrutinib/rituximab (n = 386).
Nearly three-quarters (74%) in the FCR group received six cycles of therapy, and 97% of those in the ibrutinib-rituximab group received six cycles of rituximab. Those in the ibrutinib-rituximab group also received daily doses of ibrutinib. Doses could be modified. The data cutoff was May 24, 2021.
Notably, there was no improvement in overall survival in the ibrutinib/rituximab group: 92.1% of patients lived 4 years versus 93.5% in the FCR group. This contrasts with an improvement in overall survival in the earlier E1912 study in the ibrutinib/rituximab group.
However, the study authors noted that overall survival in the FCR group is higher than in earlier studies, perhaps reflecting the wider availability of targeted therapy. The final study analysis will offer more insight into overall survival.
In an interview, hematologist David A. Bond, MD, of Ohio State University, Columbus, who is familiar with the study findings, said “the lack of an improvement in overall survival could be due to differences in available treatments at relapse, as the FLAIR study was conducted more recently than the prior E1912 study.” He added that “the younger ages in the E1912 study may have led to less risk for cardiovascular events or deaths for the patients treated with ibrutinib in the E1912 study.”
The previous E1912 trial showed a larger effect for ibrutinib/rituximab versus FCR on progression-free survival (HR, 0.37, P < .001 for E1912 and HR, 0.44, P< .0001 for the FLAIR trial). However, the study authors noted that FLAIR trial had older subjects (mean age, 62 vs 56.7 in the E1912 trial.)
As for grade 3 or 4 adverse events, leukopenia was most common in the FCR group (n = 203, 54%), compared with the ibrutinib/rituximab group (n = 55, 14%). Serious adverse events were reported in 205 (53%) of patients in the ibrutinib/rituximab group versus 203 (54%) patients in the FCR group.
All-cause infections, myelodysplastic syndrome, acute myeloid leukemia, Richter’s transformation, and other diagnosed cancers were rare but more common in the FCR group. Deaths from COVID-19 were the same at 3 in each group; 2 of 29 deaths in the FCR group and 3 of 30 deaths in the ibrutinib/rituximab group were considered to be likely linked to treatment.
Sudden unexplained or cardiac deaths were more common in the ibrutinib-rituximab group (n = 8, 2%) vs. the FCR group (n = 2, less than 1%).
Dr. Bond said “one of the takeaways for practicing hematologists from the FLAIR study is that cardiovascular complications and sudden cardiac death are clearly an issue for older patients with hypertension treated with ibrutinib. Patients should be monitored for signs or symptoms of cardiovascular disease and have close management of blood pressure.”
Dr. Burger also noted that cardiac problems are a known risk of ibrutinib. “Fortunately, we have second-generation Bruton’s tyrosine kinase inhibitors that could be chosen for patients when we are worried about side effects.”
He said that chemotherapy remains the preferred – or only – treatment in some parts of the world. And patients may prefer FCR to ibrutinib because of the latter drug’s side effects or a preference for therapy that doesn’t take as long.
The study was funded by Cancer Research UK and Janssen. The study authors reported relationships with companies such as Lilly, Janssen, AbbVie, AstraZeneca, BeiGene, Gilead, and many others. Dr. Burger reports financial support for clinical trials from Pharmacyclics, AstraZeneca, Biogen, and Janssen. Dr. Bond reported no disclosures.
The analysis of the open-label FLAIR trial, published in The Lancet Oncology, tracked 771 patients with CLL for a median follow-up of 53 months (interquartile ratio, 41-61 months) and found that median progression-free survival was not reached with ibrutinib/rituximab versus 67 months with FCR (hazard ratio, 0.44, P < .0001).
“This paper is another confirmation to say that Bruton’s tyrosine kinase inhibitors are more powerful than even our strongest chemoimmunotherapy. That’s very reassuring,” said hematologist/oncologist Jan A. Burger, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, in an interview. He did not take part in the analysis but is familiar with its findings.
There are caveats to the study. More patients in the ibrutinib/rituximab arm died of cardiac events, possibly reflecting a known risk of those drugs. And for unclear reasons, there was no difference in overall survival – a secondary endpoint – between the groups. The study authors speculate that this may be because some patients on FCR progressed and turned to effective second-line drugs.
Still, the findings are consistent with the landmark E1912 trial, the authors wrote, and adds “to a body of evidence that suggests that the use of ibrutinib-based regimens should be considered for patients with previously untreated CLL, especially those with IGHV-unmutated CLL.”
The study, partially funded by industry, was led by Peter Hillmen, PhD, of Leeds (England) Cancer Center.
According to Dr. Burger, FCR was the standard treatment for younger, fitter patients with CLL about 10-15 years ago. Then Bruton’s tyrosine kinase inhibitors such as ibrutinib entered the picture. But, as the new report notes, initial studies focused on older patients who weren’t considered fit enough to tolerate FCR.
The new study, like the E1912 trial, aimed to compare ibrutinib-rituximab versus FCR in younger, fitter patients.
From 2014 to 2018, researchers assigned 771 patients (median age, 62 years; IQR 56-67; 73% male; 95% White; 66% with World Health Organization performance status, 0) to FCR (n = 385) or ibrutinib/rituximab (n = 386).
Nearly three-quarters (74%) in the FCR group received six cycles of therapy, and 97% of those in the ibrutinib-rituximab group received six cycles of rituximab. Those in the ibrutinib-rituximab group also received daily doses of ibrutinib. Doses could be modified. The data cutoff was May 24, 2021.
Notably, there was no improvement in overall survival in the ibrutinib/rituximab group: 92.1% of patients lived 4 years versus 93.5% in the FCR group. This contrasts with an improvement in overall survival in the earlier E1912 study in the ibrutinib/rituximab group.
However, the study authors noted that overall survival in the FCR group is higher than in earlier studies, perhaps reflecting the wider availability of targeted therapy. The final study analysis will offer more insight into overall survival.
In an interview, hematologist David A. Bond, MD, of Ohio State University, Columbus, who is familiar with the study findings, said “the lack of an improvement in overall survival could be due to differences in available treatments at relapse, as the FLAIR study was conducted more recently than the prior E1912 study.” He added that “the younger ages in the E1912 study may have led to less risk for cardiovascular events or deaths for the patients treated with ibrutinib in the E1912 study.”
The previous E1912 trial showed a larger effect for ibrutinib/rituximab versus FCR on progression-free survival (HR, 0.37, P < .001 for E1912 and HR, 0.44, P< .0001 for the FLAIR trial). However, the study authors noted that FLAIR trial had older subjects (mean age, 62 vs 56.7 in the E1912 trial.)
As for grade 3 or 4 adverse events, leukopenia was most common in the FCR group (n = 203, 54%), compared with the ibrutinib/rituximab group (n = 55, 14%). Serious adverse events were reported in 205 (53%) of patients in the ibrutinib/rituximab group versus 203 (54%) patients in the FCR group.
All-cause infections, myelodysplastic syndrome, acute myeloid leukemia, Richter’s transformation, and other diagnosed cancers were rare but more common in the FCR group. Deaths from COVID-19 were the same at 3 in each group; 2 of 29 deaths in the FCR group and 3 of 30 deaths in the ibrutinib/rituximab group were considered to be likely linked to treatment.
Sudden unexplained or cardiac deaths were more common in the ibrutinib-rituximab group (n = 8, 2%) vs. the FCR group (n = 2, less than 1%).
Dr. Bond said “one of the takeaways for practicing hematologists from the FLAIR study is that cardiovascular complications and sudden cardiac death are clearly an issue for older patients with hypertension treated with ibrutinib. Patients should be monitored for signs or symptoms of cardiovascular disease and have close management of blood pressure.”
Dr. Burger also noted that cardiac problems are a known risk of ibrutinib. “Fortunately, we have second-generation Bruton’s tyrosine kinase inhibitors that could be chosen for patients when we are worried about side effects.”
He said that chemotherapy remains the preferred – or only – treatment in some parts of the world. And patients may prefer FCR to ibrutinib because of the latter drug’s side effects or a preference for therapy that doesn’t take as long.
The study was funded by Cancer Research UK and Janssen. The study authors reported relationships with companies such as Lilly, Janssen, AbbVie, AstraZeneca, BeiGene, Gilead, and many others. Dr. Burger reports financial support for clinical trials from Pharmacyclics, AstraZeneca, Biogen, and Janssen. Dr. Bond reported no disclosures.
FROM THE LANCET ONCOLOGY
Generic inhalers for COPD support hold their own
Sometimes we get what we pay for. Other times we pay too much.
That’s the message of a study published in Annals of Internal Medicine, which finds that a generic maintenance inhaler is as effective at managing symptoms of chronic obstructive pulmonary disorder (COPD) as a pricier branded alternative.
In 2019, the Food and Drug Administration approved Wixela Inhub (the combination corticosteroid/long-acting beta2 adrenergic agonist fluticasone-salmeterol; Viatris) as a generic dry powder inhaler for managing symptoms of COPD. This approval was based on evidence of the generic’s effectiveness against asthma, although COPD also was on the product label. The study authors compared Wixela’s effectiveness in controlling symptoms of COPD with that of the brand name inhaler Advair Diskus (fluticasone-salmeterol; GlaxoSmithKline), which uses the same active ingredients.
The result: “The generic looks to be as safe and effective as the brand name. I don’t see a clinical reason why one would ever need to get the brand name over the generic version,” said study author William Feldman, MD, DPhil, MPH, a health services researcher and pulmonologist at Harvard Medical School and Brigham and Women’s Hospital, both in Boston.
Same types of patients, different inhalers, same outcomes
Dr. Feldman and colleagues compared the medical records of 10,000 patients with COPD who began using the branded inhaler to the records of another 10,000 patients with COPD who opted for the generic alternative. Participants in the two groups were evenly matched by age, sex, race, and ethnicity, region, severity of COPD, and presence of other comorbidities, according to the researchers. Participants were all older than age 40, and the average age in both groups was 72 years.
The researchers looked for a difference in a first episode of a moderate exacerbation of COPD, defined as requiring a course of prednisone for 5-14 days. They also looked for cases of severe COPD exacerbation requiring hospitalization in the year after people began using either the generic or brand name inhaler. And they looked for differences across 1 year in rates of hospitalization for pneumonia.
For none of those outcomes, however, did the type of inhaler appear to matter. Compared with the brand-name drug, using the generic was associated with nearly identical rates of moderate or severe COPD exacerbation (hazard ratio, 0.97; 95% confidence interval, 0.90-1.04. The same was true for the proportion of people who went to the hospital for pneumonia at least once (HR, 0.99; 95% CI, 0.86-1.15).
“To get through the FDA as an interchangeable generic, the generic firms have to show that their product can be used in just the same way as the brand-name version,” Dr. Feldman said, which may explain why the generic and brand-name versions of the inhaler performed so similarly.
Dr. Feldman cautioned that the price savings for patients who opt for the generic over the branded product are hard to determine, given the vagaries of different insurance plans and potential rebates when using the branded project. As a general matter, having a single generic competitor will not lower costs much, Dr. Feldman noted, pointing to 2017 research from Harvard that found a profusion of generic competitors is needed to significantly lower health care costs.
“I don’t want to in any way underestimate the importance of getting that first generic onto the market, because it sets the stage for future generics,” Dr. Feldman said.
“There are very few generic options for patients with COPD,” said Surya Bhatt, MD, director of the Pulmonary Function and Exercise Physiology Lab at the University of Alabama at Birmingham. Even the rescue inhalers that people with COPD use to manage acute episodes of the condition are usually branded at this time, Dr. Bhatt noted, with few generic options.*
“The results are quite compelling,” said Dr. Bhatt, who was not involved in the research. Although the trial was not randomized, he commended the researchers for stratifying participants in the two groups to be as comparable as possible.
Dr. Bhatt noted that the FDA’s 2019 approval – given that the agency requires bioequivalence studies between branded and generic products – was enough to cause him to begin prescribing the generic inhaler. The fact that this approval was based on asthma but not also COPD is not a concern.
“There are so many similarities between asthma, COPD, and some obstructive lung diseases,” Dr. Bhatt noted.
In his experience, the only time someone with COPD continues using the branded inhaler – now that a potentially cheaper generic is available – is when their insurance plan makes their out-of-pocket cost minimal. Otherwise, brand loyalty does not exist.
“Patients are generally okay with being on a generic for inhalers, just because of the high cost,” Dr. Bhatt said.
The study was primarily supported by the National Heart, Lung, and Blood Institute. Dr. Feldman reported funding from Arnold Ventures, the Commonwealth Fund, and the FDA, and consulting relationships with Alosa Health and Aetion. Dr. Bhatt reported no relevant financial relationships.
*Correction, 8/16/23: An earlier version of this article mischaracterized Dr. Bhatt's comments on the availability of generic options.
A version of this article first appeared on Medscape.com.
Sometimes we get what we pay for. Other times we pay too much.
That’s the message of a study published in Annals of Internal Medicine, which finds that a generic maintenance inhaler is as effective at managing symptoms of chronic obstructive pulmonary disorder (COPD) as a pricier branded alternative.
In 2019, the Food and Drug Administration approved Wixela Inhub (the combination corticosteroid/long-acting beta2 adrenergic agonist fluticasone-salmeterol; Viatris) as a generic dry powder inhaler for managing symptoms of COPD. This approval was based on evidence of the generic’s effectiveness against asthma, although COPD also was on the product label. The study authors compared Wixela’s effectiveness in controlling symptoms of COPD with that of the brand name inhaler Advair Diskus (fluticasone-salmeterol; GlaxoSmithKline), which uses the same active ingredients.
The result: “The generic looks to be as safe and effective as the brand name. I don’t see a clinical reason why one would ever need to get the brand name over the generic version,” said study author William Feldman, MD, DPhil, MPH, a health services researcher and pulmonologist at Harvard Medical School and Brigham and Women’s Hospital, both in Boston.
Same types of patients, different inhalers, same outcomes
Dr. Feldman and colleagues compared the medical records of 10,000 patients with COPD who began using the branded inhaler to the records of another 10,000 patients with COPD who opted for the generic alternative. Participants in the two groups were evenly matched by age, sex, race, and ethnicity, region, severity of COPD, and presence of other comorbidities, according to the researchers. Participants were all older than age 40, and the average age in both groups was 72 years.
The researchers looked for a difference in a first episode of a moderate exacerbation of COPD, defined as requiring a course of prednisone for 5-14 days. They also looked for cases of severe COPD exacerbation requiring hospitalization in the year after people began using either the generic or brand name inhaler. And they looked for differences across 1 year in rates of hospitalization for pneumonia.
For none of those outcomes, however, did the type of inhaler appear to matter. Compared with the brand-name drug, using the generic was associated with nearly identical rates of moderate or severe COPD exacerbation (hazard ratio, 0.97; 95% confidence interval, 0.90-1.04. The same was true for the proportion of people who went to the hospital for pneumonia at least once (HR, 0.99; 95% CI, 0.86-1.15).
“To get through the FDA as an interchangeable generic, the generic firms have to show that their product can be used in just the same way as the brand-name version,” Dr. Feldman said, which may explain why the generic and brand-name versions of the inhaler performed so similarly.
Dr. Feldman cautioned that the price savings for patients who opt for the generic over the branded product are hard to determine, given the vagaries of different insurance plans and potential rebates when using the branded project. As a general matter, having a single generic competitor will not lower costs much, Dr. Feldman noted, pointing to 2017 research from Harvard that found a profusion of generic competitors is needed to significantly lower health care costs.
“I don’t want to in any way underestimate the importance of getting that first generic onto the market, because it sets the stage for future generics,” Dr. Feldman said.
“There are very few generic options for patients with COPD,” said Surya Bhatt, MD, director of the Pulmonary Function and Exercise Physiology Lab at the University of Alabama at Birmingham. Even the rescue inhalers that people with COPD use to manage acute episodes of the condition are usually branded at this time, Dr. Bhatt noted, with few generic options.*
“The results are quite compelling,” said Dr. Bhatt, who was not involved in the research. Although the trial was not randomized, he commended the researchers for stratifying participants in the two groups to be as comparable as possible.
Dr. Bhatt noted that the FDA’s 2019 approval – given that the agency requires bioequivalence studies between branded and generic products – was enough to cause him to begin prescribing the generic inhaler. The fact that this approval was based on asthma but not also COPD is not a concern.
“There are so many similarities between asthma, COPD, and some obstructive lung diseases,” Dr. Bhatt noted.
In his experience, the only time someone with COPD continues using the branded inhaler – now that a potentially cheaper generic is available – is when their insurance plan makes their out-of-pocket cost minimal. Otherwise, brand loyalty does not exist.
“Patients are generally okay with being on a generic for inhalers, just because of the high cost,” Dr. Bhatt said.
The study was primarily supported by the National Heart, Lung, and Blood Institute. Dr. Feldman reported funding from Arnold Ventures, the Commonwealth Fund, and the FDA, and consulting relationships with Alosa Health and Aetion. Dr. Bhatt reported no relevant financial relationships.
*Correction, 8/16/23: An earlier version of this article mischaracterized Dr. Bhatt's comments on the availability of generic options.
A version of this article first appeared on Medscape.com.
Sometimes we get what we pay for. Other times we pay too much.
That’s the message of a study published in Annals of Internal Medicine, which finds that a generic maintenance inhaler is as effective at managing symptoms of chronic obstructive pulmonary disorder (COPD) as a pricier branded alternative.
In 2019, the Food and Drug Administration approved Wixela Inhub (the combination corticosteroid/long-acting beta2 adrenergic agonist fluticasone-salmeterol; Viatris) as a generic dry powder inhaler for managing symptoms of COPD. This approval was based on evidence of the generic’s effectiveness against asthma, although COPD also was on the product label. The study authors compared Wixela’s effectiveness in controlling symptoms of COPD with that of the brand name inhaler Advair Diskus (fluticasone-salmeterol; GlaxoSmithKline), which uses the same active ingredients.
The result: “The generic looks to be as safe and effective as the brand name. I don’t see a clinical reason why one would ever need to get the brand name over the generic version,” said study author William Feldman, MD, DPhil, MPH, a health services researcher and pulmonologist at Harvard Medical School and Brigham and Women’s Hospital, both in Boston.
Same types of patients, different inhalers, same outcomes
Dr. Feldman and colleagues compared the medical records of 10,000 patients with COPD who began using the branded inhaler to the records of another 10,000 patients with COPD who opted for the generic alternative. Participants in the two groups were evenly matched by age, sex, race, and ethnicity, region, severity of COPD, and presence of other comorbidities, according to the researchers. Participants were all older than age 40, and the average age in both groups was 72 years.
The researchers looked for a difference in a first episode of a moderate exacerbation of COPD, defined as requiring a course of prednisone for 5-14 days. They also looked for cases of severe COPD exacerbation requiring hospitalization in the year after people began using either the generic or brand name inhaler. And they looked for differences across 1 year in rates of hospitalization for pneumonia.
For none of those outcomes, however, did the type of inhaler appear to matter. Compared with the brand-name drug, using the generic was associated with nearly identical rates of moderate or severe COPD exacerbation (hazard ratio, 0.97; 95% confidence interval, 0.90-1.04. The same was true for the proportion of people who went to the hospital for pneumonia at least once (HR, 0.99; 95% CI, 0.86-1.15).
“To get through the FDA as an interchangeable generic, the generic firms have to show that their product can be used in just the same way as the brand-name version,” Dr. Feldman said, which may explain why the generic and brand-name versions of the inhaler performed so similarly.
Dr. Feldman cautioned that the price savings for patients who opt for the generic over the branded product are hard to determine, given the vagaries of different insurance plans and potential rebates when using the branded project. As a general matter, having a single generic competitor will not lower costs much, Dr. Feldman noted, pointing to 2017 research from Harvard that found a profusion of generic competitors is needed to significantly lower health care costs.
“I don’t want to in any way underestimate the importance of getting that first generic onto the market, because it sets the stage for future generics,” Dr. Feldman said.
“There are very few generic options for patients with COPD,” said Surya Bhatt, MD, director of the Pulmonary Function and Exercise Physiology Lab at the University of Alabama at Birmingham. Even the rescue inhalers that people with COPD use to manage acute episodes of the condition are usually branded at this time, Dr. Bhatt noted, with few generic options.*
“The results are quite compelling,” said Dr. Bhatt, who was not involved in the research. Although the trial was not randomized, he commended the researchers for stratifying participants in the two groups to be as comparable as possible.
Dr. Bhatt noted that the FDA’s 2019 approval – given that the agency requires bioequivalence studies between branded and generic products – was enough to cause him to begin prescribing the generic inhaler. The fact that this approval was based on asthma but not also COPD is not a concern.
“There are so many similarities between asthma, COPD, and some obstructive lung diseases,” Dr. Bhatt noted.
In his experience, the only time someone with COPD continues using the branded inhaler – now that a potentially cheaper generic is available – is when their insurance plan makes their out-of-pocket cost minimal. Otherwise, brand loyalty does not exist.
“Patients are generally okay with being on a generic for inhalers, just because of the high cost,” Dr. Bhatt said.
The study was primarily supported by the National Heart, Lung, and Blood Institute. Dr. Feldman reported funding from Arnold Ventures, the Commonwealth Fund, and the FDA, and consulting relationships with Alosa Health and Aetion. Dr. Bhatt reported no relevant financial relationships.
*Correction, 8/16/23: An earlier version of this article mischaracterized Dr. Bhatt's comments on the availability of generic options.
A version of this article first appeared on Medscape.com.
FROM ANNALS OF INTERNAL MEDICINE
Ancestry may predict bipolar patients’ response to lithium
Lithium remains the first-line treatment for BPD, but clinical improvement occurs in less than one-third of patients, and factors that might affect response, especially genetic factors, have not been well studied, wrote Ana M. Díaz-Zuluaga, MD, of University of Antioquia, Medellín, Colombia, and colleagues.
Previous genetic research identified four linked single nucleotide polymorphisms (SNPs) in a single locus on chromosome 21 that were associated with lithium response, but the study was limited to individuals with European and Asian ancestry, the researchers said.
In a study published in the Journal of Affective Disorders, the researchers identified 172 adults aged 18 and older with a diagnosis of BPD I or II based on the DSM-IV-TR criteria. Participants had been taking lithium continuously for at least 6 months. Lithium response was defined using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with BD, also known as the Alda scale. Total Alda scale scores of 7 or higher indicated a responder phenotype; scores less than 7 were considered nonresponders.
Ancestry was determined using DNA samples and the software Structure Version 2.2, and participants were classified as Amerindian, African, or European.
The overall response rate to lithium was 15.11% (26 of 172 patients). In a univariate analysis, no significant differences emerged between responders and nonresponders in demographics or clinical characteristics. However, patients responsive to lithium were significantly less likely of African ancestry, compared with nonresponders (0.1 vs. 0.2, P = .005) and more likely of European ancestry (0.5 vs. 0.3, P = .024), and had fewer depressive episodes (2 vs. 3.9, P = .002). The difference in responders vs. nonresponders of Amerindian ancestry was not statistically significant (0.4 vs. 0.5, P = .204).
The researchers then used machine learning based on Advanced Recursive Partitioning Approaches (ARPAs) to create classification trees with and without ancestry components for predicting response to lithium. “Variable importance analysis shows that the most important predictor is the probability of Amerindian ancestry component, followed by the Amerindian and European ancestral components individual variances, and then by the African and European ancestry components,” the researchers wrote.
Without the ancestry component, the sensitivity and specificity for predicting a treatment response to lithium were 50% and 94.5% respectively, with an area under the curve of 72.2%.
“However, when ancestral components are included in the model, the sensitivity and specificity are 93 % and 84 %, respectively,” with an AUC of 89.2%, the researchers said.
Clinical predictors of treatment response included disease duration, number of depressive episodes, total number of affective episodes, and number of manic episodes.
The findings were limited by several factors including the cross-sectional design and potential impact of other psychotropic drugs, the researchers noted. A replication of the study in an independent dataset is needed to validate the findings, they said.
However, the study is the first known to explore the effect of ancestry on bipolar patients’ response to lithium, and suggests that ancestry components have potential predictive value in the clinical setting that could support a more personalized approach to treatment, the researchers said.
The study was supported by PRISMA U.T., Colciencias, Invitaci
Lithium remains the first-line treatment for BPD, but clinical improvement occurs in less than one-third of patients, and factors that might affect response, especially genetic factors, have not been well studied, wrote Ana M. Díaz-Zuluaga, MD, of University of Antioquia, Medellín, Colombia, and colleagues.
Previous genetic research identified four linked single nucleotide polymorphisms (SNPs) in a single locus on chromosome 21 that were associated with lithium response, but the study was limited to individuals with European and Asian ancestry, the researchers said.
In a study published in the Journal of Affective Disorders, the researchers identified 172 adults aged 18 and older with a diagnosis of BPD I or II based on the DSM-IV-TR criteria. Participants had been taking lithium continuously for at least 6 months. Lithium response was defined using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with BD, also known as the Alda scale. Total Alda scale scores of 7 or higher indicated a responder phenotype; scores less than 7 were considered nonresponders.
Ancestry was determined using DNA samples and the software Structure Version 2.2, and participants were classified as Amerindian, African, or European.
The overall response rate to lithium was 15.11% (26 of 172 patients). In a univariate analysis, no significant differences emerged between responders and nonresponders in demographics or clinical characteristics. However, patients responsive to lithium were significantly less likely of African ancestry, compared with nonresponders (0.1 vs. 0.2, P = .005) and more likely of European ancestry (0.5 vs. 0.3, P = .024), and had fewer depressive episodes (2 vs. 3.9, P = .002). The difference in responders vs. nonresponders of Amerindian ancestry was not statistically significant (0.4 vs. 0.5, P = .204).
The researchers then used machine learning based on Advanced Recursive Partitioning Approaches (ARPAs) to create classification trees with and without ancestry components for predicting response to lithium. “Variable importance analysis shows that the most important predictor is the probability of Amerindian ancestry component, followed by the Amerindian and European ancestral components individual variances, and then by the African and European ancestry components,” the researchers wrote.
Without the ancestry component, the sensitivity and specificity for predicting a treatment response to lithium were 50% and 94.5% respectively, with an area under the curve of 72.2%.
“However, when ancestral components are included in the model, the sensitivity and specificity are 93 % and 84 %, respectively,” with an AUC of 89.2%, the researchers said.
Clinical predictors of treatment response included disease duration, number of depressive episodes, total number of affective episodes, and number of manic episodes.
The findings were limited by several factors including the cross-sectional design and potential impact of other psychotropic drugs, the researchers noted. A replication of the study in an independent dataset is needed to validate the findings, they said.
However, the study is the first known to explore the effect of ancestry on bipolar patients’ response to lithium, and suggests that ancestry components have potential predictive value in the clinical setting that could support a more personalized approach to treatment, the researchers said.
The study was supported by PRISMA U.T., Colciencias, Invitaci
Lithium remains the first-line treatment for BPD, but clinical improvement occurs in less than one-third of patients, and factors that might affect response, especially genetic factors, have not been well studied, wrote Ana M. Díaz-Zuluaga, MD, of University of Antioquia, Medellín, Colombia, and colleagues.
Previous genetic research identified four linked single nucleotide polymorphisms (SNPs) in a single locus on chromosome 21 that were associated with lithium response, but the study was limited to individuals with European and Asian ancestry, the researchers said.
In a study published in the Journal of Affective Disorders, the researchers identified 172 adults aged 18 and older with a diagnosis of BPD I or II based on the DSM-IV-TR criteria. Participants had been taking lithium continuously for at least 6 months. Lithium response was defined using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with BD, also known as the Alda scale. Total Alda scale scores of 7 or higher indicated a responder phenotype; scores less than 7 were considered nonresponders.
Ancestry was determined using DNA samples and the software Structure Version 2.2, and participants were classified as Amerindian, African, or European.
The overall response rate to lithium was 15.11% (26 of 172 patients). In a univariate analysis, no significant differences emerged between responders and nonresponders in demographics or clinical characteristics. However, patients responsive to lithium were significantly less likely of African ancestry, compared with nonresponders (0.1 vs. 0.2, P = .005) and more likely of European ancestry (0.5 vs. 0.3, P = .024), and had fewer depressive episodes (2 vs. 3.9, P = .002). The difference in responders vs. nonresponders of Amerindian ancestry was not statistically significant (0.4 vs. 0.5, P = .204).
The researchers then used machine learning based on Advanced Recursive Partitioning Approaches (ARPAs) to create classification trees with and without ancestry components for predicting response to lithium. “Variable importance analysis shows that the most important predictor is the probability of Amerindian ancestry component, followed by the Amerindian and European ancestral components individual variances, and then by the African and European ancestry components,” the researchers wrote.
Without the ancestry component, the sensitivity and specificity for predicting a treatment response to lithium were 50% and 94.5% respectively, with an area under the curve of 72.2%.
“However, when ancestral components are included in the model, the sensitivity and specificity are 93 % and 84 %, respectively,” with an AUC of 89.2%, the researchers said.
Clinical predictors of treatment response included disease duration, number of depressive episodes, total number of affective episodes, and number of manic episodes.
The findings were limited by several factors including the cross-sectional design and potential impact of other psychotropic drugs, the researchers noted. A replication of the study in an independent dataset is needed to validate the findings, they said.
However, the study is the first known to explore the effect of ancestry on bipolar patients’ response to lithium, and suggests that ancestry components have potential predictive value in the clinical setting that could support a more personalized approach to treatment, the researchers said.
The study was supported by PRISMA U.T., Colciencias, Invitaci
FROM THE JOURNAL OF AFFECTIVE DISORDERS
Semaglutide cuts cardiovascular events in landmark trial
, in the pivotal SELECT trial, with more than 17,000 enrolled people with overweight or obesity and established cardiovascular disease (CVD), but no diabetes.
The finding should fuel improved patient access to this glucagon-like peptide-1 (GLP-1) agonist weight-loss agent that has historically been hindered by skepticism among U.S. payers, many of whom have criticized the health benefits and cost effectiveness of this drug in people whose only indication for treatment is overweight or obesity.
According to top-line results from SELECT released by Novo Nordisk on Aug. 8, the people randomly assigned to receive weekly 2.4-mg subcutaneous injections of semaglutide showed a significant 20% reduction in their incidence of the combined endpoint of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The announcement added that semaglutide treatment also significantly linked with a drop in the incidence of each of these individual three endpoints; the magnitude of these reductions, however, wasn’t specified, nor was the duration of treatment and follow-up.
The results also showed a level of safety and patient tolerance for weekly 2.4-mg injections of semaglutide that were consistent with prior reports on the agent. Semaglutide as Wegovy received marketing approval from the U.S. Food and Drug Administration in 2021 for weight loss, and in 2017 for glucose control in people with type 2 diabetes, at a weekly maximum dose of 2.0 mg (for which it’s marketed as Ozempic).
SELECT began in 2018 and randomly assigned 17,604 adults aged 45 years and older at more than 800 sites in 41 countries. The company’s announcement noted that the trial had accrued a total of 1,270 study participants with a first MACE event but did not break this total down based on treatment received.
‘A good result for patients’
“The topline results from SELECT are exciting, as preventing heart attacks and stroke with a drug that also lowers weight is very important for many patients, especially if the data also show – as I suspect they will – a meaningful improvement of quality of life for patients due to associated weight loss,” commented Naveed Sattar, PhD, a professor of metabolic medicine at the University of Glasgow who was not involved with the study.
Despite this lack of current clarity over the role that weight loss by itself played in driving the observed result, the SELECT findings seem poised to reset a long-standing prejudice against the medical necessity and safety of weight-loss agents when used for the sole indication of helping people lose weight.
Changing how obesity is regarded
“To date, there are no approved weight management medications proven to deliver effective weight management while also reducing the risk of heart attack, stroke, or cardiovascular death,” said Martin Holst Lange, executive vice president for development at Novo Nordisk, in the company’s press release.
“SELECT is a landmark trial and has demonstrated that semaglutide 2.4 mg has the potential to change how obesity is regarded and treated.”
Several of the early medical options for aiding weight loss had substantial adverse effects, including increased MACE rates, a history that led to pervasive wariness among physicians over the safety of antiobesity agents and the wisdom of using medically aided weight loss to produce health benefits.
This attitude also helped dampen health insurance coverage of weight-loss treatments. For example, Medicare has a long-standing policy against reimbursing the cost for medications that are used for the indication of weight loss, and a 2003 U.S. law prohibited part D plans from providing this coverage.
Semaglutide belongs to the class of agents that mimic the action of the incretin GLP-1. The introduction of this class of GLP-1 agonists for weight loss began in 2014 with the FDA’s approval of liraglutide (Saxenda), a daily subcutaneous injection that marked the first step toward establishing the class as safe and effective for weight loss and launching a new era in weight-loss treatment.
According to the Novo Nordisk announcement, a full report on results from SELECT will occur “at a scientific meeting later in 2023.”
SELECT is sponsored by Novo Nordisk, the company that markets semaglutide (Wegovy). Dr. Sattar is a consultant to several companies that market GLP-1 receptor agonists, including Novo Nordisk and Lilly, but has had no involvement in SELECT.
A version of this article first appeared on Medscape.com.
, in the pivotal SELECT trial, with more than 17,000 enrolled people with overweight or obesity and established cardiovascular disease (CVD), but no diabetes.
The finding should fuel improved patient access to this glucagon-like peptide-1 (GLP-1) agonist weight-loss agent that has historically been hindered by skepticism among U.S. payers, many of whom have criticized the health benefits and cost effectiveness of this drug in people whose only indication for treatment is overweight or obesity.
According to top-line results from SELECT released by Novo Nordisk on Aug. 8, the people randomly assigned to receive weekly 2.4-mg subcutaneous injections of semaglutide showed a significant 20% reduction in their incidence of the combined endpoint of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The announcement added that semaglutide treatment also significantly linked with a drop in the incidence of each of these individual three endpoints; the magnitude of these reductions, however, wasn’t specified, nor was the duration of treatment and follow-up.
The results also showed a level of safety and patient tolerance for weekly 2.4-mg injections of semaglutide that were consistent with prior reports on the agent. Semaglutide as Wegovy received marketing approval from the U.S. Food and Drug Administration in 2021 for weight loss, and in 2017 for glucose control in people with type 2 diabetes, at a weekly maximum dose of 2.0 mg (for which it’s marketed as Ozempic).
SELECT began in 2018 and randomly assigned 17,604 adults aged 45 years and older at more than 800 sites in 41 countries. The company’s announcement noted that the trial had accrued a total of 1,270 study participants with a first MACE event but did not break this total down based on treatment received.
‘A good result for patients’
“The topline results from SELECT are exciting, as preventing heart attacks and stroke with a drug that also lowers weight is very important for many patients, especially if the data also show – as I suspect they will – a meaningful improvement of quality of life for patients due to associated weight loss,” commented Naveed Sattar, PhD, a professor of metabolic medicine at the University of Glasgow who was not involved with the study.
Despite this lack of current clarity over the role that weight loss by itself played in driving the observed result, the SELECT findings seem poised to reset a long-standing prejudice against the medical necessity and safety of weight-loss agents when used for the sole indication of helping people lose weight.
Changing how obesity is regarded
“To date, there are no approved weight management medications proven to deliver effective weight management while also reducing the risk of heart attack, stroke, or cardiovascular death,” said Martin Holst Lange, executive vice president for development at Novo Nordisk, in the company’s press release.
“SELECT is a landmark trial and has demonstrated that semaglutide 2.4 mg has the potential to change how obesity is regarded and treated.”
Several of the early medical options for aiding weight loss had substantial adverse effects, including increased MACE rates, a history that led to pervasive wariness among physicians over the safety of antiobesity agents and the wisdom of using medically aided weight loss to produce health benefits.
This attitude also helped dampen health insurance coverage of weight-loss treatments. For example, Medicare has a long-standing policy against reimbursing the cost for medications that are used for the indication of weight loss, and a 2003 U.S. law prohibited part D plans from providing this coverage.
Semaglutide belongs to the class of agents that mimic the action of the incretin GLP-1. The introduction of this class of GLP-1 agonists for weight loss began in 2014 with the FDA’s approval of liraglutide (Saxenda), a daily subcutaneous injection that marked the first step toward establishing the class as safe and effective for weight loss and launching a new era in weight-loss treatment.
According to the Novo Nordisk announcement, a full report on results from SELECT will occur “at a scientific meeting later in 2023.”
SELECT is sponsored by Novo Nordisk, the company that markets semaglutide (Wegovy). Dr. Sattar is a consultant to several companies that market GLP-1 receptor agonists, including Novo Nordisk and Lilly, but has had no involvement in SELECT.
A version of this article first appeared on Medscape.com.
, in the pivotal SELECT trial, with more than 17,000 enrolled people with overweight or obesity and established cardiovascular disease (CVD), but no diabetes.
The finding should fuel improved patient access to this glucagon-like peptide-1 (GLP-1) agonist weight-loss agent that has historically been hindered by skepticism among U.S. payers, many of whom have criticized the health benefits and cost effectiveness of this drug in people whose only indication for treatment is overweight or obesity.
According to top-line results from SELECT released by Novo Nordisk on Aug. 8, the people randomly assigned to receive weekly 2.4-mg subcutaneous injections of semaglutide showed a significant 20% reduction in their incidence of the combined endpoint of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The announcement added that semaglutide treatment also significantly linked with a drop in the incidence of each of these individual three endpoints; the magnitude of these reductions, however, wasn’t specified, nor was the duration of treatment and follow-up.
The results also showed a level of safety and patient tolerance for weekly 2.4-mg injections of semaglutide that were consistent with prior reports on the agent. Semaglutide as Wegovy received marketing approval from the U.S. Food and Drug Administration in 2021 for weight loss, and in 2017 for glucose control in people with type 2 diabetes, at a weekly maximum dose of 2.0 mg (for which it’s marketed as Ozempic).
SELECT began in 2018 and randomly assigned 17,604 adults aged 45 years and older at more than 800 sites in 41 countries. The company’s announcement noted that the trial had accrued a total of 1,270 study participants with a first MACE event but did not break this total down based on treatment received.
‘A good result for patients’
“The topline results from SELECT are exciting, as preventing heart attacks and stroke with a drug that also lowers weight is very important for many patients, especially if the data also show – as I suspect they will – a meaningful improvement of quality of life for patients due to associated weight loss,” commented Naveed Sattar, PhD, a professor of metabolic medicine at the University of Glasgow who was not involved with the study.
Despite this lack of current clarity over the role that weight loss by itself played in driving the observed result, the SELECT findings seem poised to reset a long-standing prejudice against the medical necessity and safety of weight-loss agents when used for the sole indication of helping people lose weight.
Changing how obesity is regarded
“To date, there are no approved weight management medications proven to deliver effective weight management while also reducing the risk of heart attack, stroke, or cardiovascular death,” said Martin Holst Lange, executive vice president for development at Novo Nordisk, in the company’s press release.
“SELECT is a landmark trial and has demonstrated that semaglutide 2.4 mg has the potential to change how obesity is regarded and treated.”
Several of the early medical options for aiding weight loss had substantial adverse effects, including increased MACE rates, a history that led to pervasive wariness among physicians over the safety of antiobesity agents and the wisdom of using medically aided weight loss to produce health benefits.
This attitude also helped dampen health insurance coverage of weight-loss treatments. For example, Medicare has a long-standing policy against reimbursing the cost for medications that are used for the indication of weight loss, and a 2003 U.S. law prohibited part D plans from providing this coverage.
Semaglutide belongs to the class of agents that mimic the action of the incretin GLP-1. The introduction of this class of GLP-1 agonists for weight loss began in 2014 with the FDA’s approval of liraglutide (Saxenda), a daily subcutaneous injection that marked the first step toward establishing the class as safe and effective for weight loss and launching a new era in weight-loss treatment.
According to the Novo Nordisk announcement, a full report on results from SELECT will occur “at a scientific meeting later in 2023.”
SELECT is sponsored by Novo Nordisk, the company that markets semaglutide (Wegovy). Dr. Sattar is a consultant to several companies that market GLP-1 receptor agonists, including Novo Nordisk and Lilly, but has had no involvement in SELECT.
A version of this article first appeared on Medscape.com.
Drug name confusion: More than 80 new drug pairs added to the list
Zolpidem (Ambien) is a well-known sedative for sleep. Letairis (Ambrisentan) is a vasodilator for the treatment of pulmonary arterial hypertension. Citalopram (Celexa) is an antidepressant; escitalopram (Lexapro) is prescribed for anxiety and depression.
The aim is to increase awareness about the potential for a serious medication mistake when the wrong drug is given because of drug names that look and sound similar.
Awareness of these drug names, however, is just the first step in preventing medication mistakes. Health care providers should take a number of other steps as well, experts said.
ISMP launched its confusing drug names list, previously called look-alike, sound-alike (LASA) drugs, in 2008. The new list is an update of the 2019 version, said Michael J. Gaunt, PharmD, senior manager of error reporting programs for the ISMP, which focuses on the prevention of medication mistakes. The new entries were chosen on the basis of a number of factors, including ISMP’s analysis of recent medication mishap reports that were submitted to it.
The ISMP list now includes about 528 drug pairs, Dr. Gaunt said. The list is long, he said, partly because each pair is listed twice, so readers can cross reference. For instance, hydralazine and hydroxyzine are listed in one entry in the list, and hydroxyzine and hydralazine are listed in another.
Brand Institute in Miami has named, among other drugs, Entresto, Rybelsus, and Lunesta. The regulatory arm of the company, the Drug Safety Institute, “considers drug names that have been confused as an important part of our comprehensive drug name assessments,” Todd Bridges, global president of the institute, said in an emailed statement. Information on the confusing drug names are incorporated into the company’s proprietary algorithm and is used when developing brand names for drugs. “We continually update this algorithm as new drug names that are often confused are identified,” Mr. Bridges said.
Confusing drug names: Ongoing issue
The length of the list, as well as the latest additions, are not surprising, said Mary Ann Kliethermes, PharmD, director of medication safety and quality for the American Society of Health-System Pharmacists, a membership organization of about 60,000 pharmacists who practice in inpatient and outpatient settings.
“I’ve been in practice over 45 years,” she said, “and this has been a problem ever since I have been in practice.” The sheer volume of new drugs is one reason, she said. From 2013 through 2022, the U.S. Food and Drug Administration approved an average of 43 novel drugs per year, according to a report from its Center for Drug Evaluation and Research. “Since the 90s, this [confusion about similar drug names] has happened,” Dr. Kliethermes said.
According to a 2023 report, about 7,000-9,000 people die each year in the United States as the result of a medication error. However, it’s impossible to say for sure what percentage of those errors involve name confusion, Dr. Gaunt said.
Not all the mistakes are reported. Some that are reported are dramatic and deadly. In 2022, a Tennessee nurse was convicted of gross neglect and negligent homicide. She was sentenced to 3 years’ probation after she mistakenly gave vercuronium, an anesthetic agent, instead of the sedative Versed to a patient, and the woman died.
Updated list: A closer look
Many of the new drug pairs that are listed in the update are cephalosporins, said Dr. Kliethermes, who reviewed the new list for this news organization. In all, 20 of the latest 82 additions are cephalosporins. These include drugs such as cefazolin, which can be confused with cefotetan, and vice versa. These drugs have been around since the 1980s, she said, but “they needed to be on there.” Even in the 1980s, it was becoming difficult to differentiate them, and there were fewer drugs in that class then, she said.
Influenza vaccines made the new list, too. Fluzone High-Dose Quadrivalent can be confused with fluzone quadrivalent. Other new additions: hydrochlorothiazide and hydroxychloroquine, Lasik and Wakix, Pitressin and Pitocin, Remeron and Rozerem.
Beyond the list
While it’s not possible to pinpoint how big a problem name confusion is in causing medication mistakes, “it is certainly still an issue,” Dr. Gaunt said. A variety of practices can reduce that risk substantially, Dr. Gaunt and Dr. Kliethermes agreed.
Tall-man lettering. Both the FDA and the ISMP recommend the use of so-called tall-man lettering (TML), which involves the use of uppercase letters, sometimes in boldface, to distinguish similar names on product labels and elsewhere. Examples include vinBLAStine and vinCRIStine.
Electronic prescribing. “It eliminates the risk of handwriting confusion,” Dr. Gaunt said. However, electronic prescribing can have a downside, Dr. Kliethermes said. When ordering medication, a person may type in a few letters and may then be presented with a prompt that lists several drug names, and it can be easy to click the wrong one. For that reason, ISMP and other experts recommend typing at least five letters when searching for a medication in an electronic system.
Use both brand and generic names on labels and prescriptions.
Write the indication. That can serve as a double check. If a prescription for Ambien says “For sleep,” there’s probably less risk of filling a prescription for ambrisentan, the vasodilator.
Smart formulary additions. When hospitals add medications to their formularies, “part of that formulary assessment should include looking at the potential risk for errors,” Dr. Gaunt said. This involves keeping an eye out for confusing names and similar packaging. “Do that analysis up front and put in strategies to minimize that. Maybe you look for a different drug [for the same use] that has a different name.” Or choose a different manufacturer, so the medication would at least have a different container.
Use bar code scanning. Suppose a pharmacist goes to the shelf and pulls the wrong drug. “Bar code scanning provides the opportunity to catch the error,” Dr. Gaunt said. Many community pharmacies now have bar code scanning. ISMP just issued best practices for community pharmacies, Dr. Gaunt said, and these include the use of bar code scanning and other measures.
Educate consumers. Health care providers can educate consumers on how to minimize the risk of getting the wrong drug, Dr. Gaunt said. When patients are picking up a prescription, suggest they look at the container label; if it looks different from previous prescriptions of the same medicine, ask the pharmacist for an explanation. Some patients just pass it off, Dr. Gaunt said, figuring the pharmacist or health plan switched manufacturers of their medication.
Access the list. The entire list is on the ISMP site and is accessible after free registration.
Goal: Preventing confusion
The FDA has provided guidance for industry on naming drugs not yet approved so that the proposed names are not too similar in sound or appearance to those already on the market. Included in the lengthy document are checklists, such as, “Across a range of dialects, are the names consistently pronounced differently?” and “Are the lengths of the names dissimilar when scripted?” (Lengths are considered different if they differ by two or more letters.)
The FDA also offers the phonetic and orthographic computer analysis (POCA) program, a software tool that employs an advanced algorithm to evaluate similarities between two drug names. The data sources are updated regularly as new drugs are approved.
Liability update
The problem may be decreasing. In a 2020 report, researchers used pharmacists’ professional liability claim data from the Healthcare Providers Service Organization. They compared 2018 data on claims with 2013 data. The percentage of claims associated with wrong drug dispensing errors declined from 43.8% in 2013 to 36.8% in 2018. Wrong dose claims also declined, from 31.5% to 15.3%.
These researchers concluded that technology and automation have contributed to the prevention of medication errors caused by the use of the wrong drug and the wrong dose, but mistakes continue, owing to system and human errors.
A version of this article first appeared on Medscape.com.
Zolpidem (Ambien) is a well-known sedative for sleep. Letairis (Ambrisentan) is a vasodilator for the treatment of pulmonary arterial hypertension. Citalopram (Celexa) is an antidepressant; escitalopram (Lexapro) is prescribed for anxiety and depression.
The aim is to increase awareness about the potential for a serious medication mistake when the wrong drug is given because of drug names that look and sound similar.
Awareness of these drug names, however, is just the first step in preventing medication mistakes. Health care providers should take a number of other steps as well, experts said.
ISMP launched its confusing drug names list, previously called look-alike, sound-alike (LASA) drugs, in 2008. The new list is an update of the 2019 version, said Michael J. Gaunt, PharmD, senior manager of error reporting programs for the ISMP, which focuses on the prevention of medication mistakes. The new entries were chosen on the basis of a number of factors, including ISMP’s analysis of recent medication mishap reports that were submitted to it.
The ISMP list now includes about 528 drug pairs, Dr. Gaunt said. The list is long, he said, partly because each pair is listed twice, so readers can cross reference. For instance, hydralazine and hydroxyzine are listed in one entry in the list, and hydroxyzine and hydralazine are listed in another.
Brand Institute in Miami has named, among other drugs, Entresto, Rybelsus, and Lunesta. The regulatory arm of the company, the Drug Safety Institute, “considers drug names that have been confused as an important part of our comprehensive drug name assessments,” Todd Bridges, global president of the institute, said in an emailed statement. Information on the confusing drug names are incorporated into the company’s proprietary algorithm and is used when developing brand names for drugs. “We continually update this algorithm as new drug names that are often confused are identified,” Mr. Bridges said.
Confusing drug names: Ongoing issue
The length of the list, as well as the latest additions, are not surprising, said Mary Ann Kliethermes, PharmD, director of medication safety and quality for the American Society of Health-System Pharmacists, a membership organization of about 60,000 pharmacists who practice in inpatient and outpatient settings.
“I’ve been in practice over 45 years,” she said, “and this has been a problem ever since I have been in practice.” The sheer volume of new drugs is one reason, she said. From 2013 through 2022, the U.S. Food and Drug Administration approved an average of 43 novel drugs per year, according to a report from its Center for Drug Evaluation and Research. “Since the 90s, this [confusion about similar drug names] has happened,” Dr. Kliethermes said.
According to a 2023 report, about 7,000-9,000 people die each year in the United States as the result of a medication error. However, it’s impossible to say for sure what percentage of those errors involve name confusion, Dr. Gaunt said.
Not all the mistakes are reported. Some that are reported are dramatic and deadly. In 2022, a Tennessee nurse was convicted of gross neglect and negligent homicide. She was sentenced to 3 years’ probation after she mistakenly gave vercuronium, an anesthetic agent, instead of the sedative Versed to a patient, and the woman died.
Updated list: A closer look
Many of the new drug pairs that are listed in the update are cephalosporins, said Dr. Kliethermes, who reviewed the new list for this news organization. In all, 20 of the latest 82 additions are cephalosporins. These include drugs such as cefazolin, which can be confused with cefotetan, and vice versa. These drugs have been around since the 1980s, she said, but “they needed to be on there.” Even in the 1980s, it was becoming difficult to differentiate them, and there were fewer drugs in that class then, she said.
Influenza vaccines made the new list, too. Fluzone High-Dose Quadrivalent can be confused with fluzone quadrivalent. Other new additions: hydrochlorothiazide and hydroxychloroquine, Lasik and Wakix, Pitressin and Pitocin, Remeron and Rozerem.
Beyond the list
While it’s not possible to pinpoint how big a problem name confusion is in causing medication mistakes, “it is certainly still an issue,” Dr. Gaunt said. A variety of practices can reduce that risk substantially, Dr. Gaunt and Dr. Kliethermes agreed.
Tall-man lettering. Both the FDA and the ISMP recommend the use of so-called tall-man lettering (TML), which involves the use of uppercase letters, sometimes in boldface, to distinguish similar names on product labels and elsewhere. Examples include vinBLAStine and vinCRIStine.
Electronic prescribing. “It eliminates the risk of handwriting confusion,” Dr. Gaunt said. However, electronic prescribing can have a downside, Dr. Kliethermes said. When ordering medication, a person may type in a few letters and may then be presented with a prompt that lists several drug names, and it can be easy to click the wrong one. For that reason, ISMP and other experts recommend typing at least five letters when searching for a medication in an electronic system.
Use both brand and generic names on labels and prescriptions.
Write the indication. That can serve as a double check. If a prescription for Ambien says “For sleep,” there’s probably less risk of filling a prescription for ambrisentan, the vasodilator.
Smart formulary additions. When hospitals add medications to their formularies, “part of that formulary assessment should include looking at the potential risk for errors,” Dr. Gaunt said. This involves keeping an eye out for confusing names and similar packaging. “Do that analysis up front and put in strategies to minimize that. Maybe you look for a different drug [for the same use] that has a different name.” Or choose a different manufacturer, so the medication would at least have a different container.
Use bar code scanning. Suppose a pharmacist goes to the shelf and pulls the wrong drug. “Bar code scanning provides the opportunity to catch the error,” Dr. Gaunt said. Many community pharmacies now have bar code scanning. ISMP just issued best practices for community pharmacies, Dr. Gaunt said, and these include the use of bar code scanning and other measures.
Educate consumers. Health care providers can educate consumers on how to minimize the risk of getting the wrong drug, Dr. Gaunt said. When patients are picking up a prescription, suggest they look at the container label; if it looks different from previous prescriptions of the same medicine, ask the pharmacist for an explanation. Some patients just pass it off, Dr. Gaunt said, figuring the pharmacist or health plan switched manufacturers of their medication.
Access the list. The entire list is on the ISMP site and is accessible after free registration.
Goal: Preventing confusion
The FDA has provided guidance for industry on naming drugs not yet approved so that the proposed names are not too similar in sound or appearance to those already on the market. Included in the lengthy document are checklists, such as, “Across a range of dialects, are the names consistently pronounced differently?” and “Are the lengths of the names dissimilar when scripted?” (Lengths are considered different if they differ by two or more letters.)
The FDA also offers the phonetic and orthographic computer analysis (POCA) program, a software tool that employs an advanced algorithm to evaluate similarities between two drug names. The data sources are updated regularly as new drugs are approved.
Liability update
The problem may be decreasing. In a 2020 report, researchers used pharmacists’ professional liability claim data from the Healthcare Providers Service Organization. They compared 2018 data on claims with 2013 data. The percentage of claims associated with wrong drug dispensing errors declined from 43.8% in 2013 to 36.8% in 2018. Wrong dose claims also declined, from 31.5% to 15.3%.
These researchers concluded that technology and automation have contributed to the prevention of medication errors caused by the use of the wrong drug and the wrong dose, but mistakes continue, owing to system and human errors.
A version of this article first appeared on Medscape.com.
Zolpidem (Ambien) is a well-known sedative for sleep. Letairis (Ambrisentan) is a vasodilator for the treatment of pulmonary arterial hypertension. Citalopram (Celexa) is an antidepressant; escitalopram (Lexapro) is prescribed for anxiety and depression.
The aim is to increase awareness about the potential for a serious medication mistake when the wrong drug is given because of drug names that look and sound similar.
Awareness of these drug names, however, is just the first step in preventing medication mistakes. Health care providers should take a number of other steps as well, experts said.
ISMP launched its confusing drug names list, previously called look-alike, sound-alike (LASA) drugs, in 2008. The new list is an update of the 2019 version, said Michael J. Gaunt, PharmD, senior manager of error reporting programs for the ISMP, which focuses on the prevention of medication mistakes. The new entries were chosen on the basis of a number of factors, including ISMP’s analysis of recent medication mishap reports that were submitted to it.
The ISMP list now includes about 528 drug pairs, Dr. Gaunt said. The list is long, he said, partly because each pair is listed twice, so readers can cross reference. For instance, hydralazine and hydroxyzine are listed in one entry in the list, and hydroxyzine and hydralazine are listed in another.
Brand Institute in Miami has named, among other drugs, Entresto, Rybelsus, and Lunesta. The regulatory arm of the company, the Drug Safety Institute, “considers drug names that have been confused as an important part of our comprehensive drug name assessments,” Todd Bridges, global president of the institute, said in an emailed statement. Information on the confusing drug names are incorporated into the company’s proprietary algorithm and is used when developing brand names for drugs. “We continually update this algorithm as new drug names that are often confused are identified,” Mr. Bridges said.
Confusing drug names: Ongoing issue
The length of the list, as well as the latest additions, are not surprising, said Mary Ann Kliethermes, PharmD, director of medication safety and quality for the American Society of Health-System Pharmacists, a membership organization of about 60,000 pharmacists who practice in inpatient and outpatient settings.
“I’ve been in practice over 45 years,” she said, “and this has been a problem ever since I have been in practice.” The sheer volume of new drugs is one reason, she said. From 2013 through 2022, the U.S. Food and Drug Administration approved an average of 43 novel drugs per year, according to a report from its Center for Drug Evaluation and Research. “Since the 90s, this [confusion about similar drug names] has happened,” Dr. Kliethermes said.
According to a 2023 report, about 7,000-9,000 people die each year in the United States as the result of a medication error. However, it’s impossible to say for sure what percentage of those errors involve name confusion, Dr. Gaunt said.
Not all the mistakes are reported. Some that are reported are dramatic and deadly. In 2022, a Tennessee nurse was convicted of gross neglect and negligent homicide. She was sentenced to 3 years’ probation after she mistakenly gave vercuronium, an anesthetic agent, instead of the sedative Versed to a patient, and the woman died.
Updated list: A closer look
Many of the new drug pairs that are listed in the update are cephalosporins, said Dr. Kliethermes, who reviewed the new list for this news organization. In all, 20 of the latest 82 additions are cephalosporins. These include drugs such as cefazolin, which can be confused with cefotetan, and vice versa. These drugs have been around since the 1980s, she said, but “they needed to be on there.” Even in the 1980s, it was becoming difficult to differentiate them, and there were fewer drugs in that class then, she said.
Influenza vaccines made the new list, too. Fluzone High-Dose Quadrivalent can be confused with fluzone quadrivalent. Other new additions: hydrochlorothiazide and hydroxychloroquine, Lasik and Wakix, Pitressin and Pitocin, Remeron and Rozerem.
Beyond the list
While it’s not possible to pinpoint how big a problem name confusion is in causing medication mistakes, “it is certainly still an issue,” Dr. Gaunt said. A variety of practices can reduce that risk substantially, Dr. Gaunt and Dr. Kliethermes agreed.
Tall-man lettering. Both the FDA and the ISMP recommend the use of so-called tall-man lettering (TML), which involves the use of uppercase letters, sometimes in boldface, to distinguish similar names on product labels and elsewhere. Examples include vinBLAStine and vinCRIStine.
Electronic prescribing. “It eliminates the risk of handwriting confusion,” Dr. Gaunt said. However, electronic prescribing can have a downside, Dr. Kliethermes said. When ordering medication, a person may type in a few letters and may then be presented with a prompt that lists several drug names, and it can be easy to click the wrong one. For that reason, ISMP and other experts recommend typing at least five letters when searching for a medication in an electronic system.
Use both brand and generic names on labels and prescriptions.
Write the indication. That can serve as a double check. If a prescription for Ambien says “For sleep,” there’s probably less risk of filling a prescription for ambrisentan, the vasodilator.
Smart formulary additions. When hospitals add medications to their formularies, “part of that formulary assessment should include looking at the potential risk for errors,” Dr. Gaunt said. This involves keeping an eye out for confusing names and similar packaging. “Do that analysis up front and put in strategies to minimize that. Maybe you look for a different drug [for the same use] that has a different name.” Or choose a different manufacturer, so the medication would at least have a different container.
Use bar code scanning. Suppose a pharmacist goes to the shelf and pulls the wrong drug. “Bar code scanning provides the opportunity to catch the error,” Dr. Gaunt said. Many community pharmacies now have bar code scanning. ISMP just issued best practices for community pharmacies, Dr. Gaunt said, and these include the use of bar code scanning and other measures.
Educate consumers. Health care providers can educate consumers on how to minimize the risk of getting the wrong drug, Dr. Gaunt said. When patients are picking up a prescription, suggest they look at the container label; if it looks different from previous prescriptions of the same medicine, ask the pharmacist for an explanation. Some patients just pass it off, Dr. Gaunt said, figuring the pharmacist or health plan switched manufacturers of their medication.
Access the list. The entire list is on the ISMP site and is accessible after free registration.
Goal: Preventing confusion
The FDA has provided guidance for industry on naming drugs not yet approved so that the proposed names are not too similar in sound or appearance to those already on the market. Included in the lengthy document are checklists, such as, “Across a range of dialects, are the names consistently pronounced differently?” and “Are the lengths of the names dissimilar when scripted?” (Lengths are considered different if they differ by two or more letters.)
The FDA also offers the phonetic and orthographic computer analysis (POCA) program, a software tool that employs an advanced algorithm to evaluate similarities between two drug names. The data sources are updated regularly as new drugs are approved.
Liability update
The problem may be decreasing. In a 2020 report, researchers used pharmacists’ professional liability claim data from the Healthcare Providers Service Organization. They compared 2018 data on claims with 2013 data. The percentage of claims associated with wrong drug dispensing errors declined from 43.8% in 2013 to 36.8% in 2018. Wrong dose claims also declined, from 31.5% to 15.3%.
These researchers concluded that technology and automation have contributed to the prevention of medication errors caused by the use of the wrong drug and the wrong dose, but mistakes continue, owing to system and human errors.
A version of this article first appeared on Medscape.com.