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FDA approves first drug for treatment of resistant cytomegalovirus infection
The Food and Drug Administration has approved the first treatment for posttransplant cytomegalovirus (CMV) that is resistant to other drugs.
There are an estimated 200,000 adult transplants every year globally. CMV, a type of herpes virus, is one of the most common infections in transplant patients, occurring in 16%-56% of solid organ transplant recipients and 30%-70% of hematopoietic stem cell transplant recipients, according to Takeda Pharmaceutical Company Limited, the company that manufactures Livtencity. For immunosuppressed transplant patients, CMV infection can lead to complications that include loss of the transplanted or organ or even death.
“Cytomegalovirus infections that are resistant or do not respond to available drugs are of even greater concern,” John Farley, MD, MPH, the director of the Office of Infectious Diseases in the FDA’s Center for Drug Evaluation and Research, said in a statement. “Today’s approval helps meet a significant unmet medical need by providing a treatment option for this patient population.”
Livtencity, which is taken orally, works by preventing the activity of the enzyme responsible for virus replication. The approval, announced Nov. 23, was based on a phase 3 clinical trial that compared Livtencity with conventional antiviral treatments in the achievement of CMV DNA concentration levels below what is measurable in transplant patients with CMV infection that is refractory or treatment-resistant. After 8 weeks, of the 235 patients who received Livtencity, 56% achieved this primary endpoint, compared with 24% of the 117 patients who received conventional antiviral treatments, the press release says.
The most reported adverse reactions of Livtencity were taste disturbance, nausea, diarrhea, vomiting, and fatigue.
“We are grateful for the contributions of the patients and clinicians who participated in our clinical trials, as well as the dedication of our scientists and researchers,” Ramona Sequeira, president of the Takeda’s U.S. Business Unit and Global Portfolio Commercialization, said in a statement. “People undergoing transplants have a lengthy and complex health care journey; with the approval of this treatment, we’re proud to offer these individuals a new oral antiviral to fight CMV infection and disease.”
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved the first treatment for posttransplant cytomegalovirus (CMV) that is resistant to other drugs.
There are an estimated 200,000 adult transplants every year globally. CMV, a type of herpes virus, is one of the most common infections in transplant patients, occurring in 16%-56% of solid organ transplant recipients and 30%-70% of hematopoietic stem cell transplant recipients, according to Takeda Pharmaceutical Company Limited, the company that manufactures Livtencity. For immunosuppressed transplant patients, CMV infection can lead to complications that include loss of the transplanted or organ or even death.
“Cytomegalovirus infections that are resistant or do not respond to available drugs are of even greater concern,” John Farley, MD, MPH, the director of the Office of Infectious Diseases in the FDA’s Center for Drug Evaluation and Research, said in a statement. “Today’s approval helps meet a significant unmet medical need by providing a treatment option for this patient population.”
Livtencity, which is taken orally, works by preventing the activity of the enzyme responsible for virus replication. The approval, announced Nov. 23, was based on a phase 3 clinical trial that compared Livtencity with conventional antiviral treatments in the achievement of CMV DNA concentration levels below what is measurable in transplant patients with CMV infection that is refractory or treatment-resistant. After 8 weeks, of the 235 patients who received Livtencity, 56% achieved this primary endpoint, compared with 24% of the 117 patients who received conventional antiviral treatments, the press release says.
The most reported adverse reactions of Livtencity were taste disturbance, nausea, diarrhea, vomiting, and fatigue.
“We are grateful for the contributions of the patients and clinicians who participated in our clinical trials, as well as the dedication of our scientists and researchers,” Ramona Sequeira, president of the Takeda’s U.S. Business Unit and Global Portfolio Commercialization, said in a statement. “People undergoing transplants have a lengthy and complex health care journey; with the approval of this treatment, we’re proud to offer these individuals a new oral antiviral to fight CMV infection and disease.”
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved the first treatment for posttransplant cytomegalovirus (CMV) that is resistant to other drugs.
There are an estimated 200,000 adult transplants every year globally. CMV, a type of herpes virus, is one of the most common infections in transplant patients, occurring in 16%-56% of solid organ transplant recipients and 30%-70% of hematopoietic stem cell transplant recipients, according to Takeda Pharmaceutical Company Limited, the company that manufactures Livtencity. For immunosuppressed transplant patients, CMV infection can lead to complications that include loss of the transplanted or organ or even death.
“Cytomegalovirus infections that are resistant or do not respond to available drugs are of even greater concern,” John Farley, MD, MPH, the director of the Office of Infectious Diseases in the FDA’s Center for Drug Evaluation and Research, said in a statement. “Today’s approval helps meet a significant unmet medical need by providing a treatment option for this patient population.”
Livtencity, which is taken orally, works by preventing the activity of the enzyme responsible for virus replication. The approval, announced Nov. 23, was based on a phase 3 clinical trial that compared Livtencity with conventional antiviral treatments in the achievement of CMV DNA concentration levels below what is measurable in transplant patients with CMV infection that is refractory or treatment-resistant. After 8 weeks, of the 235 patients who received Livtencity, 56% achieved this primary endpoint, compared with 24% of the 117 patients who received conventional antiviral treatments, the press release says.
The most reported adverse reactions of Livtencity were taste disturbance, nausea, diarrhea, vomiting, and fatigue.
“We are grateful for the contributions of the patients and clinicians who participated in our clinical trials, as well as the dedication of our scientists and researchers,” Ramona Sequeira, president of the Takeda’s U.S. Business Unit and Global Portfolio Commercialization, said in a statement. “People undergoing transplants have a lengthy and complex health care journey; with the approval of this treatment, we’re proud to offer these individuals a new oral antiviral to fight CMV infection and disease.”
A version of this article first appeared on Medscape.com.
Three drugs go head-to-head in advanced lung cancer study
The findings were reported in JAMA Network Open.
“Until recently, chemotherapy with platinum doublet was the standard first-line option for most patients with advanced NSCLC who did not have these genetic drivers or were not tested for them and remains the first choice in many parts of the world,” wrote the authors of the study which was led by Sreeram Ramagopalan, PhD, of F. Hoffmann-La Roche in Switzerland which funded the study.
Atezolizumab (Tecentriq, Genentech), which was approved in October by the U.S. Food and Drug Administration, is a monoclonal antibody that targets programmed cell death ligand 1 (PD-L1). It is also approved as monotherapy for patients with advanced NSCLC whose disease progressed despite treatment with platinum-based chemotherapy.
This is the first-known analysis that compares atezolizumab, nivolumab (Opdivo, Bristol Myers Squibb), and docetaxel (Taxotere, Sanofi) in patients outside of clinical trials, said Vivek Subbiah, MD, of MD Anderson Cancer Center and the study’s first author. “We have several new immune checkpoint inhibitors approved for treatment for NSCLC. Head-to-head comparison of the effectiveness of these agents in the real world are lacking,” he said.
Treatment with immune checkpoint inhibitors has shown improvement in the survival of patients with advanced NSCLC who failed chemotherapy treatment.
This study included 3,336 patients (mean age 67 years, 54.6% men) with advanced NSCLC who were treated with platinum-based chemotherapy. Data were collected from more than 1,000 clinics in the United States. Of the patients, 206 received atezolizumab, 500 received docetaxel, and 2,630 received nivolumab.
Patients were followed between May 2011 and March 2020. Atezolizumab and nivolumab showed a similar overall survival in these patients, but atezolizumab showed a longer overall survival, compared with docetaxel.
“Compared with docetaxel, atezolizumab was associated with significantly longer survival in the overall population and across all subgroups analyzed,” including patients with stage IIIB or IV cancer at diagnosis and nonsquamous NSCLC, the authors wrote. “Atezolizumab was associated with longer overall survival compared with docetaxel and was on par with nivolumab, supporting current clinical guidelines for systemic therapy for patients with advanced NSCLC in the U.S.”
Limitations of the study included its observational design and a small number of patients receiving atezolizumab. The authors suggested that studies using larger sample sizes are needed.
This study was funded by F. Hoffmann-La Roche. Genentech is a subsidiary of F. Hoffmann-La Roche.
The findings were reported in JAMA Network Open.
“Until recently, chemotherapy with platinum doublet was the standard first-line option for most patients with advanced NSCLC who did not have these genetic drivers or were not tested for them and remains the first choice in many parts of the world,” wrote the authors of the study which was led by Sreeram Ramagopalan, PhD, of F. Hoffmann-La Roche in Switzerland which funded the study.
Atezolizumab (Tecentriq, Genentech), which was approved in October by the U.S. Food and Drug Administration, is a monoclonal antibody that targets programmed cell death ligand 1 (PD-L1). It is also approved as monotherapy for patients with advanced NSCLC whose disease progressed despite treatment with platinum-based chemotherapy.
This is the first-known analysis that compares atezolizumab, nivolumab (Opdivo, Bristol Myers Squibb), and docetaxel (Taxotere, Sanofi) in patients outside of clinical trials, said Vivek Subbiah, MD, of MD Anderson Cancer Center and the study’s first author. “We have several new immune checkpoint inhibitors approved for treatment for NSCLC. Head-to-head comparison of the effectiveness of these agents in the real world are lacking,” he said.
Treatment with immune checkpoint inhibitors has shown improvement in the survival of patients with advanced NSCLC who failed chemotherapy treatment.
This study included 3,336 patients (mean age 67 years, 54.6% men) with advanced NSCLC who were treated with platinum-based chemotherapy. Data were collected from more than 1,000 clinics in the United States. Of the patients, 206 received atezolizumab, 500 received docetaxel, and 2,630 received nivolumab.
Patients were followed between May 2011 and March 2020. Atezolizumab and nivolumab showed a similar overall survival in these patients, but atezolizumab showed a longer overall survival, compared with docetaxel.
“Compared with docetaxel, atezolizumab was associated with significantly longer survival in the overall population and across all subgroups analyzed,” including patients with stage IIIB or IV cancer at diagnosis and nonsquamous NSCLC, the authors wrote. “Atezolizumab was associated with longer overall survival compared with docetaxel and was on par with nivolumab, supporting current clinical guidelines for systemic therapy for patients with advanced NSCLC in the U.S.”
Limitations of the study included its observational design and a small number of patients receiving atezolizumab. The authors suggested that studies using larger sample sizes are needed.
This study was funded by F. Hoffmann-La Roche. Genentech is a subsidiary of F. Hoffmann-La Roche.
The findings were reported in JAMA Network Open.
“Until recently, chemotherapy with platinum doublet was the standard first-line option for most patients with advanced NSCLC who did not have these genetic drivers or were not tested for them and remains the first choice in many parts of the world,” wrote the authors of the study which was led by Sreeram Ramagopalan, PhD, of F. Hoffmann-La Roche in Switzerland which funded the study.
Atezolizumab (Tecentriq, Genentech), which was approved in October by the U.S. Food and Drug Administration, is a monoclonal antibody that targets programmed cell death ligand 1 (PD-L1). It is also approved as monotherapy for patients with advanced NSCLC whose disease progressed despite treatment with platinum-based chemotherapy.
This is the first-known analysis that compares atezolizumab, nivolumab (Opdivo, Bristol Myers Squibb), and docetaxel (Taxotere, Sanofi) in patients outside of clinical trials, said Vivek Subbiah, MD, of MD Anderson Cancer Center and the study’s first author. “We have several new immune checkpoint inhibitors approved for treatment for NSCLC. Head-to-head comparison of the effectiveness of these agents in the real world are lacking,” he said.
Treatment with immune checkpoint inhibitors has shown improvement in the survival of patients with advanced NSCLC who failed chemotherapy treatment.
This study included 3,336 patients (mean age 67 years, 54.6% men) with advanced NSCLC who were treated with platinum-based chemotherapy. Data were collected from more than 1,000 clinics in the United States. Of the patients, 206 received atezolizumab, 500 received docetaxel, and 2,630 received nivolumab.
Patients were followed between May 2011 and March 2020. Atezolizumab and nivolumab showed a similar overall survival in these patients, but atezolizumab showed a longer overall survival, compared with docetaxel.
“Compared with docetaxel, atezolizumab was associated with significantly longer survival in the overall population and across all subgroups analyzed,” including patients with stage IIIB or IV cancer at diagnosis and nonsquamous NSCLC, the authors wrote. “Atezolizumab was associated with longer overall survival compared with docetaxel and was on par with nivolumab, supporting current clinical guidelines for systemic therapy for patients with advanced NSCLC in the U.S.”
Limitations of the study included its observational design and a small number of patients receiving atezolizumab. The authors suggested that studies using larger sample sizes are needed.
This study was funded by F. Hoffmann-La Roche. Genentech is a subsidiary of F. Hoffmann-La Roche.
FROM JAMA NETWORK OPEN
Lithium’s antisuicidal effects questioned
Adding lithium to usual care does not decrease the risk of suicide-related events in those with major depressive disorder (MDD) or bipolar disorder (BD) who have survived a recent suicidal event, new research shows.
The results of a randomized, double-blind, placebo-controlled trial in veterans showed no apparent advantage of the drug in preventing self-injury, suicide attempts, or urgent hospitalization to prevent suicide.
“Lithium is an important therapy for bipolar disorders and depression subsets. Our study indicates that, in patients who are actively followed and treated in a system of care that the VA provides, simply adding lithium to their existing management, including medications, is unlikely to be effective for preventing a broad range of suicide-related events,” study investigator Ryan Ferguson, MPH, ScD, Boston Cooperative Studies Coordinating Center, VA Boston Healthcare System, told this news organization.
The study was published online JAMA Psychiatry.
Surprising findings
The results were somewhat surprising, Dr. Ferguson added. “Lithium showed little or no effect in our study, compared to observational data and results from previous trials. Many clinicians and practice guidelines had assumed that lithium was an effective agent in preventing suicide,” he said.
However, the authors of an accompanying editorial urge caution in concluding that lithium has no antisuicidal effects.
This “rigorously designed and conducted trial has much to teach but cannot be taken as evidence that lithium treatment is ineffective regarding suicidal risk,” write Ross Baldessarini, MD, and Leonardo Tondo, MD, department of psychiatry, Harvard Medical School, Boston.
Study participants were veterans with MDD or BD receiving care at one of 29 Veterans Administration medical centers who survived a recent suicide-related event. In addition to usual care, they were randomly assigned to receive oral extended-release lithium carbonate starting at 600 mg/day or matching placebo for 52 weeks.
The primary outcome was time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide.
The trial was stopped for futility after 519 veterans (mean age, 42.8 years; 84% male) were randomly assigned to receive lithium (n = 255) or placebo (n = 264). At 3 months, mean lithium concentrations were 0.54 mEq/L for patients with BD and 0.46 mEq/L for those with MDD.
There was no significant difference in the primary outcome (hazard ratio, 1.10; 95% confidence interval, 0.77-1.55; P = .61).
One death occurred in the lithium group and three in the placebo group. There were no unanticipated drug-related safety concerns.
Caveats, cautionary notes
The researchers note that the study did not reach its original recruitment goal. “One of the barriers to recruitment was the perception of many of the clinicians caring for potential participants that the effectiveness of lithium was already established; in fact, this perception was supported by the VA/U.S. Department of Defense Clinical Practice Guideline,” they point out.
They also note that most veterans in the study had depression rather than BD, which is the most common indication for lithium use. Most also had substance use disorders, posttraumatic stress disorder, or both, which could influence outcomes.
As a result of small numbers, it wasn’t possible to evaluate outcomes for patients with BD, test whether outcomes differed among patients with BD and MDD, or assess whether comorbidities attenuated the effects of lithium.
The study’s protocol increased participants’ contacts with the VA, which also may have affected outcomes, the researchers note.
In addition, high rates of attrition and low rates of substantial adherence to lithium meant only about half (48.1%) of the study population achieved target serum lithium concentrations.
Editorial writers Dr. Baldessarini and Dr. Tondo note that the low circulating concentrations of lithium and the fact that adherence to assigned treatment was considered adequate in only 17% of participants are key limitations of the study.
“In general, controlled treatment trials aimed at detecting suicide preventive effects are difficult to design, perform, and interpret,” they point out.
Evidence supporting an antisuicidal effect of lithium treatment includes nearly three dozen observational trials that have shown fewer suicides or attempts with lithium treatment, as well as “marked, temporary” increases in suicidal behavior soon after stopping lithium treatment.
Dr. Baldessarini and Dr. Tondo note the current findings “cannot be taken as evidence that lithium lacks antisuicidal effects. An ironic final note is that recruiting participants to such trials may be made difficult by an evidently prevalent belief that the question of antisuicidal effects of lithium is already settled, which it certainly is not,” they write.
Dr. Ferguson “agrees that more work needs to be done to understand the antisuicidal effect of lithium.
The study received financial and material support from a grant from the Cooperative Studies Program, Office of Research and Development, U.S. Department of Veterans Affairs. Dr. Ferguson has disclosed no relevant financial relationships. A complete list of author disclosures is available with the original article.
Dr. Baldessarini and Dr. Tondo have disclosed no relevant financial relationships. Their editorial was supported by grants from the Bruce J. Anderson Foundation, the McLean Private Donors Fund for Psychiatric Research, and the Aretaeus Foundation of Rome.
A version of this article first appeared on Medscape.com.
Adding lithium to usual care does not decrease the risk of suicide-related events in those with major depressive disorder (MDD) or bipolar disorder (BD) who have survived a recent suicidal event, new research shows.
The results of a randomized, double-blind, placebo-controlled trial in veterans showed no apparent advantage of the drug in preventing self-injury, suicide attempts, or urgent hospitalization to prevent suicide.
“Lithium is an important therapy for bipolar disorders and depression subsets. Our study indicates that, in patients who are actively followed and treated in a system of care that the VA provides, simply adding lithium to their existing management, including medications, is unlikely to be effective for preventing a broad range of suicide-related events,” study investigator Ryan Ferguson, MPH, ScD, Boston Cooperative Studies Coordinating Center, VA Boston Healthcare System, told this news organization.
The study was published online JAMA Psychiatry.
Surprising findings
The results were somewhat surprising, Dr. Ferguson added. “Lithium showed little or no effect in our study, compared to observational data and results from previous trials. Many clinicians and practice guidelines had assumed that lithium was an effective agent in preventing suicide,” he said.
However, the authors of an accompanying editorial urge caution in concluding that lithium has no antisuicidal effects.
This “rigorously designed and conducted trial has much to teach but cannot be taken as evidence that lithium treatment is ineffective regarding suicidal risk,” write Ross Baldessarini, MD, and Leonardo Tondo, MD, department of psychiatry, Harvard Medical School, Boston.
Study participants were veterans with MDD or BD receiving care at one of 29 Veterans Administration medical centers who survived a recent suicide-related event. In addition to usual care, they were randomly assigned to receive oral extended-release lithium carbonate starting at 600 mg/day or matching placebo for 52 weeks.
The primary outcome was time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide.
The trial was stopped for futility after 519 veterans (mean age, 42.8 years; 84% male) were randomly assigned to receive lithium (n = 255) or placebo (n = 264). At 3 months, mean lithium concentrations were 0.54 mEq/L for patients with BD and 0.46 mEq/L for those with MDD.
There was no significant difference in the primary outcome (hazard ratio, 1.10; 95% confidence interval, 0.77-1.55; P = .61).
One death occurred in the lithium group and three in the placebo group. There were no unanticipated drug-related safety concerns.
Caveats, cautionary notes
The researchers note that the study did not reach its original recruitment goal. “One of the barriers to recruitment was the perception of many of the clinicians caring for potential participants that the effectiveness of lithium was already established; in fact, this perception was supported by the VA/U.S. Department of Defense Clinical Practice Guideline,” they point out.
They also note that most veterans in the study had depression rather than BD, which is the most common indication for lithium use. Most also had substance use disorders, posttraumatic stress disorder, or both, which could influence outcomes.
As a result of small numbers, it wasn’t possible to evaluate outcomes for patients with BD, test whether outcomes differed among patients with BD and MDD, or assess whether comorbidities attenuated the effects of lithium.
The study’s protocol increased participants’ contacts with the VA, which also may have affected outcomes, the researchers note.
In addition, high rates of attrition and low rates of substantial adherence to lithium meant only about half (48.1%) of the study population achieved target serum lithium concentrations.
Editorial writers Dr. Baldessarini and Dr. Tondo note that the low circulating concentrations of lithium and the fact that adherence to assigned treatment was considered adequate in only 17% of participants are key limitations of the study.
“In general, controlled treatment trials aimed at detecting suicide preventive effects are difficult to design, perform, and interpret,” they point out.
Evidence supporting an antisuicidal effect of lithium treatment includes nearly three dozen observational trials that have shown fewer suicides or attempts with lithium treatment, as well as “marked, temporary” increases in suicidal behavior soon after stopping lithium treatment.
Dr. Baldessarini and Dr. Tondo note the current findings “cannot be taken as evidence that lithium lacks antisuicidal effects. An ironic final note is that recruiting participants to such trials may be made difficult by an evidently prevalent belief that the question of antisuicidal effects of lithium is already settled, which it certainly is not,” they write.
Dr. Ferguson “agrees that more work needs to be done to understand the antisuicidal effect of lithium.
The study received financial and material support from a grant from the Cooperative Studies Program, Office of Research and Development, U.S. Department of Veterans Affairs. Dr. Ferguson has disclosed no relevant financial relationships. A complete list of author disclosures is available with the original article.
Dr. Baldessarini and Dr. Tondo have disclosed no relevant financial relationships. Their editorial was supported by grants from the Bruce J. Anderson Foundation, the McLean Private Donors Fund for Psychiatric Research, and the Aretaeus Foundation of Rome.
A version of this article first appeared on Medscape.com.
Adding lithium to usual care does not decrease the risk of suicide-related events in those with major depressive disorder (MDD) or bipolar disorder (BD) who have survived a recent suicidal event, new research shows.
The results of a randomized, double-blind, placebo-controlled trial in veterans showed no apparent advantage of the drug in preventing self-injury, suicide attempts, or urgent hospitalization to prevent suicide.
“Lithium is an important therapy for bipolar disorders and depression subsets. Our study indicates that, in patients who are actively followed and treated in a system of care that the VA provides, simply adding lithium to their existing management, including medications, is unlikely to be effective for preventing a broad range of suicide-related events,” study investigator Ryan Ferguson, MPH, ScD, Boston Cooperative Studies Coordinating Center, VA Boston Healthcare System, told this news organization.
The study was published online JAMA Psychiatry.
Surprising findings
The results were somewhat surprising, Dr. Ferguson added. “Lithium showed little or no effect in our study, compared to observational data and results from previous trials. Many clinicians and practice guidelines had assumed that lithium was an effective agent in preventing suicide,” he said.
However, the authors of an accompanying editorial urge caution in concluding that lithium has no antisuicidal effects.
This “rigorously designed and conducted trial has much to teach but cannot be taken as evidence that lithium treatment is ineffective regarding suicidal risk,” write Ross Baldessarini, MD, and Leonardo Tondo, MD, department of psychiatry, Harvard Medical School, Boston.
Study participants were veterans with MDD or BD receiving care at one of 29 Veterans Administration medical centers who survived a recent suicide-related event. In addition to usual care, they were randomly assigned to receive oral extended-release lithium carbonate starting at 600 mg/day or matching placebo for 52 weeks.
The primary outcome was time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide.
The trial was stopped for futility after 519 veterans (mean age, 42.8 years; 84% male) were randomly assigned to receive lithium (n = 255) or placebo (n = 264). At 3 months, mean lithium concentrations were 0.54 mEq/L for patients with BD and 0.46 mEq/L for those with MDD.
There was no significant difference in the primary outcome (hazard ratio, 1.10; 95% confidence interval, 0.77-1.55; P = .61).
One death occurred in the lithium group and three in the placebo group. There were no unanticipated drug-related safety concerns.
Caveats, cautionary notes
The researchers note that the study did not reach its original recruitment goal. “One of the barriers to recruitment was the perception of many of the clinicians caring for potential participants that the effectiveness of lithium was already established; in fact, this perception was supported by the VA/U.S. Department of Defense Clinical Practice Guideline,” they point out.
They also note that most veterans in the study had depression rather than BD, which is the most common indication for lithium use. Most also had substance use disorders, posttraumatic stress disorder, or both, which could influence outcomes.
As a result of small numbers, it wasn’t possible to evaluate outcomes for patients with BD, test whether outcomes differed among patients with BD and MDD, or assess whether comorbidities attenuated the effects of lithium.
The study’s protocol increased participants’ contacts with the VA, which also may have affected outcomes, the researchers note.
In addition, high rates of attrition and low rates of substantial adherence to lithium meant only about half (48.1%) of the study population achieved target serum lithium concentrations.
Editorial writers Dr. Baldessarini and Dr. Tondo note that the low circulating concentrations of lithium and the fact that adherence to assigned treatment was considered adequate in only 17% of participants are key limitations of the study.
“In general, controlled treatment trials aimed at detecting suicide preventive effects are difficult to design, perform, and interpret,” they point out.
Evidence supporting an antisuicidal effect of lithium treatment includes nearly three dozen observational trials that have shown fewer suicides or attempts with lithium treatment, as well as “marked, temporary” increases in suicidal behavior soon after stopping lithium treatment.
Dr. Baldessarini and Dr. Tondo note the current findings “cannot be taken as evidence that lithium lacks antisuicidal effects. An ironic final note is that recruiting participants to such trials may be made difficult by an evidently prevalent belief that the question of antisuicidal effects of lithium is already settled, which it certainly is not,” they write.
Dr. Ferguson “agrees that more work needs to be done to understand the antisuicidal effect of lithium.
The study received financial and material support from a grant from the Cooperative Studies Program, Office of Research and Development, U.S. Department of Veterans Affairs. Dr. Ferguson has disclosed no relevant financial relationships. A complete list of author disclosures is available with the original article.
Dr. Baldessarini and Dr. Tondo have disclosed no relevant financial relationships. Their editorial was supported by grants from the Bruce J. Anderson Foundation, the McLean Private Donors Fund for Psychiatric Research, and the Aretaeus Foundation of Rome.
A version of this article first appeared on Medscape.com.
FROM JAMA PSYCHIATRY
Advanced CKD doesn’t derail empagliflozin in EMPEROR-preserved
More than half of the nearly 6,000 patients with heart failure and HFpEF enrolled in EMPEROR-Preserved had CKD (although renal function was not an enrollment criterion), including 10% with an estimated glomerular filtration rate (eGFR) that fell in the range of 20-29 mL/min/1.73 m2, which categorized them as having stage 4 CKD.
The results showed, in a prespecified analysis, that treatment with empagliflozin led to a consistent, significant relative risk reduction compared with placebo in the primary endpoint of cardiovascular death or hospitalization for heart failure “across the full spectrum of kidney function, down to an eGFR of 20 mL/min/1.73m2,” said Faiez Zannad, MD, PhD, who presented the findings at the annual meeting of the American Society of Nephrology.
Among the 46.5% of enrolled patients without CKD, empagliflozin produced a significant 20% drop in the primary outcome relative to those who received placebo. Among the 53.5% of patients with CKD at time of randomization (defined as an eGFR <60 mL/min/1/73 m2 or a urinary albumin to creatinine ratio >300 mg/g), treatment with empagliflozin was associated with a significant 25% cut in the primary endpoint compared with placebo.
Empagliflozin was also “well tolerated” by patients with HFpEF, whether or not they also had CKD, “including patients with severely impaired kidney function,” said Dr. Zannad, a professor of cardiology therapeutics at the University of Lorraine in Nancy, France, at the virtual meeting.
An end to ‘renalism’
“This is a nail in the coffin for the concept of ‘renalism,’” the erroneous notion held by many clinicians and researchers that various treatments are not as effective and potentially more likely to cause adverse effects in patients with CKD compared with those with better renal function, commented Janani Rangaswami, MD, a nephrologist who is a professor and director of the cardiorenal program at George Washington University, Washington, D.C.
In addition to EMPEROR-Preserved, other large trials of agents from the SGLT2 inhibitor class bucked the premise of renalism and took the “groundbreaking step” of enrolling patients with moderate-severe CKD, noted Dr. Rangaswami in an interview. In particular, two trials took this approach when enrolling patients with heart failure with reduced ejection fraction (HFrEF), EMPEROR-Reduced (which also tested empagliflozin and matched the design of EMPEROR-Preserved) and DAPA-HF (which tested the SGLT2 inhibitor dapagliflozin [Farxiga, AstraZeneca]).
“It was a huge, bold step, especially in EMPEROR-Preserved and in EMPEROR-Reduced, which both enrolled patients with eGFRs as low as 20 mL/min/1.73m2,” Dr. Rangaswami said. DAPA-HF included patients with eGFRs as low as 30 mL/min/1.73m2.
EMPEROR-Reduced and DAPA-HF – published earlier this year – both had similar findings as EMPEROR-Preserved as reported by Dr. Zannad: consistent benefit from empagliflozin or dapagliflozin regardless of eGFR level and no signal of increased adverse events from treatment.
In fact, all three analyses show that patients with worse renal function had the highest risk for cardiovascular death and hospitalization for heart failure; hence, the beneficial impact from SGLT2 inhibitors is greatest in these patients.
These observations “make it easier to focus on the group with moderate-to-severe CKD,” both in the routine care setting as well as in future trials, said Dr. Rangaswami.
“This is a welcome trend that paves the way to test more treatments in patients with stage 4 and even stage 5 CKD, patients ... excluded from trials in the past,” she said.
In addition, the consistent benefit from SGLT2 inhibitors in these three heart failure trials regardless of CKD “means there is simply no room for renalism. There is no room for clinicians to say that because a patient’s eGFR is 30 mL/min/1.73m2 they are worried about starting an SGLT2 inhibitor,” she stressed.
More CKD-independent effects of empagliflozin
Results of other new analyses from EMPEROR-Preserved, also reported by Dr. Zannad, included the finding that empagliflozin was associated with a similar slowing of loss of renal function over time compared with placebo, regardless of CKD status.
In patients with CKD, empagliflozin slowed eGFR loss by 1.4 mL/min/1.73 m2/year, and in those without CKD, by 1.3 mL/min/1.73 m2/year, relative to placebo.
“Even in patients without CKD, there was a relevant eGFR decline in the placebo group that was attenuated by empagliflozin,” Dr. Zannad said.
At the end of the study, when empagliflozin was stopped, patients with or without CKD had their eGFR bounce back by an identical 2.4 mL/min/1.73 m2 relative to placebo.
Empagliflozin slowed progression to macroalbuminuria and significantly reduced the incidence of acute kidney injury by a similar amount regardless of CKD status compared with placebo.
EMPEROR-Preserved enrolled patients with function-limiting HFpEF, a left ventricular ejection fraction >40%, and a minimum level of a reliable serum marker of heart failure, N-terminal pro-B-type natriuretic peptide (NT-proBNP). Compared with placebo, empagliflozin reduced the trial’s primary outcome by an absolute 3.3 percentage points and by a significant relative risk reduction of 21% after a median 26 months of follow-up, according to a report published in October 2021.
EMPEROR-Preserved is the first prospective, randomized trial to unequivocally show the efficacy and safety of a drug for improving outcomes in patients with HFpEF.
EMPEROR-Preserved was sponsored by Boehringer-Ingelheim and Lilly, which market empagliflozin (Jardiance). Dr. Zannad has reported financial relationships with Boehringer Ingelheim as well as other companies. Dr. Rangaswami has reported being a consultant for Boehringer Ingelheim, Lilly, and AstraZeneca.
A version of this article first appeared on Medscape.com.
More than half of the nearly 6,000 patients with heart failure and HFpEF enrolled in EMPEROR-Preserved had CKD (although renal function was not an enrollment criterion), including 10% with an estimated glomerular filtration rate (eGFR) that fell in the range of 20-29 mL/min/1.73 m2, which categorized them as having stage 4 CKD.
The results showed, in a prespecified analysis, that treatment with empagliflozin led to a consistent, significant relative risk reduction compared with placebo in the primary endpoint of cardiovascular death or hospitalization for heart failure “across the full spectrum of kidney function, down to an eGFR of 20 mL/min/1.73m2,” said Faiez Zannad, MD, PhD, who presented the findings at the annual meeting of the American Society of Nephrology.
Among the 46.5% of enrolled patients without CKD, empagliflozin produced a significant 20% drop in the primary outcome relative to those who received placebo. Among the 53.5% of patients with CKD at time of randomization (defined as an eGFR <60 mL/min/1/73 m2 or a urinary albumin to creatinine ratio >300 mg/g), treatment with empagliflozin was associated with a significant 25% cut in the primary endpoint compared with placebo.
Empagliflozin was also “well tolerated” by patients with HFpEF, whether or not they also had CKD, “including patients with severely impaired kidney function,” said Dr. Zannad, a professor of cardiology therapeutics at the University of Lorraine in Nancy, France, at the virtual meeting.
An end to ‘renalism’
“This is a nail in the coffin for the concept of ‘renalism,’” the erroneous notion held by many clinicians and researchers that various treatments are not as effective and potentially more likely to cause adverse effects in patients with CKD compared with those with better renal function, commented Janani Rangaswami, MD, a nephrologist who is a professor and director of the cardiorenal program at George Washington University, Washington, D.C.
In addition to EMPEROR-Preserved, other large trials of agents from the SGLT2 inhibitor class bucked the premise of renalism and took the “groundbreaking step” of enrolling patients with moderate-severe CKD, noted Dr. Rangaswami in an interview. In particular, two trials took this approach when enrolling patients with heart failure with reduced ejection fraction (HFrEF), EMPEROR-Reduced (which also tested empagliflozin and matched the design of EMPEROR-Preserved) and DAPA-HF (which tested the SGLT2 inhibitor dapagliflozin [Farxiga, AstraZeneca]).
“It was a huge, bold step, especially in EMPEROR-Preserved and in EMPEROR-Reduced, which both enrolled patients with eGFRs as low as 20 mL/min/1.73m2,” Dr. Rangaswami said. DAPA-HF included patients with eGFRs as low as 30 mL/min/1.73m2.
EMPEROR-Reduced and DAPA-HF – published earlier this year – both had similar findings as EMPEROR-Preserved as reported by Dr. Zannad: consistent benefit from empagliflozin or dapagliflozin regardless of eGFR level and no signal of increased adverse events from treatment.
In fact, all three analyses show that patients with worse renal function had the highest risk for cardiovascular death and hospitalization for heart failure; hence, the beneficial impact from SGLT2 inhibitors is greatest in these patients.
These observations “make it easier to focus on the group with moderate-to-severe CKD,” both in the routine care setting as well as in future trials, said Dr. Rangaswami.
“This is a welcome trend that paves the way to test more treatments in patients with stage 4 and even stage 5 CKD, patients ... excluded from trials in the past,” she said.
In addition, the consistent benefit from SGLT2 inhibitors in these three heart failure trials regardless of CKD “means there is simply no room for renalism. There is no room for clinicians to say that because a patient’s eGFR is 30 mL/min/1.73m2 they are worried about starting an SGLT2 inhibitor,” she stressed.
More CKD-independent effects of empagliflozin
Results of other new analyses from EMPEROR-Preserved, also reported by Dr. Zannad, included the finding that empagliflozin was associated with a similar slowing of loss of renal function over time compared with placebo, regardless of CKD status.
In patients with CKD, empagliflozin slowed eGFR loss by 1.4 mL/min/1.73 m2/year, and in those without CKD, by 1.3 mL/min/1.73 m2/year, relative to placebo.
“Even in patients without CKD, there was a relevant eGFR decline in the placebo group that was attenuated by empagliflozin,” Dr. Zannad said.
At the end of the study, when empagliflozin was stopped, patients with or without CKD had their eGFR bounce back by an identical 2.4 mL/min/1.73 m2 relative to placebo.
Empagliflozin slowed progression to macroalbuminuria and significantly reduced the incidence of acute kidney injury by a similar amount regardless of CKD status compared with placebo.
EMPEROR-Preserved enrolled patients with function-limiting HFpEF, a left ventricular ejection fraction >40%, and a minimum level of a reliable serum marker of heart failure, N-terminal pro-B-type natriuretic peptide (NT-proBNP). Compared with placebo, empagliflozin reduced the trial’s primary outcome by an absolute 3.3 percentage points and by a significant relative risk reduction of 21% after a median 26 months of follow-up, according to a report published in October 2021.
EMPEROR-Preserved is the first prospective, randomized trial to unequivocally show the efficacy and safety of a drug for improving outcomes in patients with HFpEF.
EMPEROR-Preserved was sponsored by Boehringer-Ingelheim and Lilly, which market empagliflozin (Jardiance). Dr. Zannad has reported financial relationships with Boehringer Ingelheim as well as other companies. Dr. Rangaswami has reported being a consultant for Boehringer Ingelheim, Lilly, and AstraZeneca.
A version of this article first appeared on Medscape.com.
More than half of the nearly 6,000 patients with heart failure and HFpEF enrolled in EMPEROR-Preserved had CKD (although renal function was not an enrollment criterion), including 10% with an estimated glomerular filtration rate (eGFR) that fell in the range of 20-29 mL/min/1.73 m2, which categorized them as having stage 4 CKD.
The results showed, in a prespecified analysis, that treatment with empagliflozin led to a consistent, significant relative risk reduction compared with placebo in the primary endpoint of cardiovascular death or hospitalization for heart failure “across the full spectrum of kidney function, down to an eGFR of 20 mL/min/1.73m2,” said Faiez Zannad, MD, PhD, who presented the findings at the annual meeting of the American Society of Nephrology.
Among the 46.5% of enrolled patients without CKD, empagliflozin produced a significant 20% drop in the primary outcome relative to those who received placebo. Among the 53.5% of patients with CKD at time of randomization (defined as an eGFR <60 mL/min/1/73 m2 or a urinary albumin to creatinine ratio >300 mg/g), treatment with empagliflozin was associated with a significant 25% cut in the primary endpoint compared with placebo.
Empagliflozin was also “well tolerated” by patients with HFpEF, whether or not they also had CKD, “including patients with severely impaired kidney function,” said Dr. Zannad, a professor of cardiology therapeutics at the University of Lorraine in Nancy, France, at the virtual meeting.
An end to ‘renalism’
“This is a nail in the coffin for the concept of ‘renalism,’” the erroneous notion held by many clinicians and researchers that various treatments are not as effective and potentially more likely to cause adverse effects in patients with CKD compared with those with better renal function, commented Janani Rangaswami, MD, a nephrologist who is a professor and director of the cardiorenal program at George Washington University, Washington, D.C.
In addition to EMPEROR-Preserved, other large trials of agents from the SGLT2 inhibitor class bucked the premise of renalism and took the “groundbreaking step” of enrolling patients with moderate-severe CKD, noted Dr. Rangaswami in an interview. In particular, two trials took this approach when enrolling patients with heart failure with reduced ejection fraction (HFrEF), EMPEROR-Reduced (which also tested empagliflozin and matched the design of EMPEROR-Preserved) and DAPA-HF (which tested the SGLT2 inhibitor dapagliflozin [Farxiga, AstraZeneca]).
“It was a huge, bold step, especially in EMPEROR-Preserved and in EMPEROR-Reduced, which both enrolled patients with eGFRs as low as 20 mL/min/1.73m2,” Dr. Rangaswami said. DAPA-HF included patients with eGFRs as low as 30 mL/min/1.73m2.
EMPEROR-Reduced and DAPA-HF – published earlier this year – both had similar findings as EMPEROR-Preserved as reported by Dr. Zannad: consistent benefit from empagliflozin or dapagliflozin regardless of eGFR level and no signal of increased adverse events from treatment.
In fact, all three analyses show that patients with worse renal function had the highest risk for cardiovascular death and hospitalization for heart failure; hence, the beneficial impact from SGLT2 inhibitors is greatest in these patients.
These observations “make it easier to focus on the group with moderate-to-severe CKD,” both in the routine care setting as well as in future trials, said Dr. Rangaswami.
“This is a welcome trend that paves the way to test more treatments in patients with stage 4 and even stage 5 CKD, patients ... excluded from trials in the past,” she said.
In addition, the consistent benefit from SGLT2 inhibitors in these three heart failure trials regardless of CKD “means there is simply no room for renalism. There is no room for clinicians to say that because a patient’s eGFR is 30 mL/min/1.73m2 they are worried about starting an SGLT2 inhibitor,” she stressed.
More CKD-independent effects of empagliflozin
Results of other new analyses from EMPEROR-Preserved, also reported by Dr. Zannad, included the finding that empagliflozin was associated with a similar slowing of loss of renal function over time compared with placebo, regardless of CKD status.
In patients with CKD, empagliflozin slowed eGFR loss by 1.4 mL/min/1.73 m2/year, and in those without CKD, by 1.3 mL/min/1.73 m2/year, relative to placebo.
“Even in patients without CKD, there was a relevant eGFR decline in the placebo group that was attenuated by empagliflozin,” Dr. Zannad said.
At the end of the study, when empagliflozin was stopped, patients with or without CKD had their eGFR bounce back by an identical 2.4 mL/min/1.73 m2 relative to placebo.
Empagliflozin slowed progression to macroalbuminuria and significantly reduced the incidence of acute kidney injury by a similar amount regardless of CKD status compared with placebo.
EMPEROR-Preserved enrolled patients with function-limiting HFpEF, a left ventricular ejection fraction >40%, and a minimum level of a reliable serum marker of heart failure, N-terminal pro-B-type natriuretic peptide (NT-proBNP). Compared with placebo, empagliflozin reduced the trial’s primary outcome by an absolute 3.3 percentage points and by a significant relative risk reduction of 21% after a median 26 months of follow-up, according to a report published in October 2021.
EMPEROR-Preserved is the first prospective, randomized trial to unequivocally show the efficacy and safety of a drug for improving outcomes in patients with HFpEF.
EMPEROR-Preserved was sponsored by Boehringer-Ingelheim and Lilly, which market empagliflozin (Jardiance). Dr. Zannad has reported financial relationships with Boehringer Ingelheim as well as other companies. Dr. Rangaswami has reported being a consultant for Boehringer Ingelheim, Lilly, and AstraZeneca.
A version of this article first appeared on Medscape.com.
FROM KIDNEY WEEK 2021
Empagliflozin a winner in challenging arena of stabilized acute HF
The sodium-glucose transporter 2 inhibitors, relative newcomers among first-line agents for chronic heart failure (HF), could well attain the same go-to status in patients hospitalized with acute HF if the EMPULSE trial has anything to say about it.
Of the study’s 530 such patients, those started on daily empagliflozin (Jardiance) soon after they were stabilized, compared with a control group, were less likely to die or be rehospitalized for HF over the next 3 months.
Also, “we saw an improvement in quality of life, we saw a greater reduction in body weight, and we didn’t see any safety concerns in this very vulnerable and sick patient population,” Adriaan A. Voors, MD, University Medical Center Groningen (the Netherlands), said when presenting the trial at the American Heart Association scientific sessions.
Patients assigned to empagliflozin had a 36% greater likelihood of showing a benefit as reflected in the treatment’s win ratio when opposed by placebo, an emerging way to express outcomes in cardiovascular clinical trials. The SGLT2 inhibitor’s win ratio for the primary endpoint was 1.36 (95% confidence interval, 1.09-1.68, P = .0054), Dr. Voors reported. The outcome consisted of death, number of HF events, time to first HF event, and 90-day change in quality of life scores.
There is reluctance in practice to start patients that early after decompensation on drugs used in chronic HF, Dr. Voors said in an interview. Empagliflozin in the trial was initiated in the stabilized setting an average of 3 days after hospital admission, he said. The trial should reassure physicians that the drug “is not only safe to start early in hospital, but it’s also beneficial to start early in hospital.”
EMPULSE, combined with support from other recent trials, “should be clinical practice changing, with early in-hospital initiation of SGLT2 inhibitors in patients hospitalized with HF being the expectation, along with clear recognition that delaying SGLT2 inhibitor initiation may expose patients to unnecessary harms and delays in improved health status,” Gregg C. Fonarow, MD, University of California Los Angeles Medical Center, told this news organization.
“For patients with HF, irrespective of ejection fraction, early in-hospital initiation of SGLT2 inhibitors – once stabilized and in the absence of contraindications – should be considered a new standard of care,” said Fonarow, who was not part of EMPULSE.
The trial also lends new weight to the strategy of “simultaneous or rapid-sequence initiation” of the so-called four pillars of guideline-directed medical therapy of HF with reduced ejection fraction in patients hospitalized with HFrEF, once they are stabilized, Dr. Fonarow said. The four-pronged approach, he noted, consists of sacubitril/valsartan (Entresto), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor.
Indeed, the new findings “fill an important gap and are clearly practice changing,” agreed Nancy K. Sweitzer, MD, PhD, University of Arizona Sarver Heart Center, Tucson, as an invited discussant following Dr. Voors’ presentation. “Few therapies have been shown to impact the course of those hospitalized with acute decompensated heart failure.”
Of note in the trial, Dr. Sweitzer continued, patients were started on empagliflozin regardless of any drug therapy they might already be on for chronic HF. “Because patients in the EMPULSE trial could be enrolled with a new diagnosis of heart failure, they were, by definition, not all on chronic guideline-directed heart failure therapy. Nevertheless, such patients benefited equally from the study intervention,” she said.
“This is crucial, as it tells us these drugs have immediate and important effects and should not be withheld while other drug classes are initiated and optimized.”
EMPULSE entered patients hospitalized for acute HF, which could be de novo or a decompensation of chronic HF, without regard to ejection fraction or whether they had diabetes, and who were clinically stable after at least one dose of loop diuretics. Their ejection fractions averaged 35% and exceeded 40% in about one-third of the total cohort.
At 90 days in the win ratio analysis, the 265 patients assigned to empagliflozin 10 mg once daily were the “winners”; that is, they were more likely to show a clinical benefit about 54% of the time in paired match-ups of patient outcomes, compared with about 40% for the 265 in the control group. The match-ups were a tie 6.4% of the time.
The empagliflozin group also benefited significantly for the endpoint of death from any cause or first HF event, with a hazard ratio of 0.65 (95% CI, 0.43-0.99; P = .042). They also were less likely to experience acute renal failure (7.7% vs. 12.1% for the control group) or serious adverse events (32.3% vs. 43.6%), Dr. Voors reported.
Tempting as it might be, the findings can’t necessarily be generalized to other SGLT2 inhibitors without an evidence base. But as Dr. Voors observed, several ongoing trials are exploring dapagliflozin (Farxiga) in a similar clinical setting.
They include DICTATE-AHF in patients with diabetes admitted with acute HF, and DAPA ACT HF-TIMI 68, which is entering patients stabilized during hospitalization with acute decompensated HFrEF. The trials are scheduled for completion in 2022 and 2023, respectively.
EMPULSE was supported by the Boehringer Ingelheim–Eli Lilly Diabetes Alliance. Dr. Voors disclosed research support and consulting for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Myokardia, Novo Nordisk, Novartis, and Roche Diagnostics. Dr. Sweitzer disclosed honoraria from Acorda and Myokardia, and reported receiving research support from Novartis and Merck. Dr. Fonarow cited honoraria from Abbott, Amgen, Janssen, Medtronic, Bayer, Merck, AstraZeneca, Cytokinetics, and Novartis.
A version of this article first appeared on Medscape.com.
The sodium-glucose transporter 2 inhibitors, relative newcomers among first-line agents for chronic heart failure (HF), could well attain the same go-to status in patients hospitalized with acute HF if the EMPULSE trial has anything to say about it.
Of the study’s 530 such patients, those started on daily empagliflozin (Jardiance) soon after they were stabilized, compared with a control group, were less likely to die or be rehospitalized for HF over the next 3 months.
Also, “we saw an improvement in quality of life, we saw a greater reduction in body weight, and we didn’t see any safety concerns in this very vulnerable and sick patient population,” Adriaan A. Voors, MD, University Medical Center Groningen (the Netherlands), said when presenting the trial at the American Heart Association scientific sessions.
Patients assigned to empagliflozin had a 36% greater likelihood of showing a benefit as reflected in the treatment’s win ratio when opposed by placebo, an emerging way to express outcomes in cardiovascular clinical trials. The SGLT2 inhibitor’s win ratio for the primary endpoint was 1.36 (95% confidence interval, 1.09-1.68, P = .0054), Dr. Voors reported. The outcome consisted of death, number of HF events, time to first HF event, and 90-day change in quality of life scores.
There is reluctance in practice to start patients that early after decompensation on drugs used in chronic HF, Dr. Voors said in an interview. Empagliflozin in the trial was initiated in the stabilized setting an average of 3 days after hospital admission, he said. The trial should reassure physicians that the drug “is not only safe to start early in hospital, but it’s also beneficial to start early in hospital.”
EMPULSE, combined with support from other recent trials, “should be clinical practice changing, with early in-hospital initiation of SGLT2 inhibitors in patients hospitalized with HF being the expectation, along with clear recognition that delaying SGLT2 inhibitor initiation may expose patients to unnecessary harms and delays in improved health status,” Gregg C. Fonarow, MD, University of California Los Angeles Medical Center, told this news organization.
“For patients with HF, irrespective of ejection fraction, early in-hospital initiation of SGLT2 inhibitors – once stabilized and in the absence of contraindications – should be considered a new standard of care,” said Fonarow, who was not part of EMPULSE.
The trial also lends new weight to the strategy of “simultaneous or rapid-sequence initiation” of the so-called four pillars of guideline-directed medical therapy of HF with reduced ejection fraction in patients hospitalized with HFrEF, once they are stabilized, Dr. Fonarow said. The four-pronged approach, he noted, consists of sacubitril/valsartan (Entresto), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor.
Indeed, the new findings “fill an important gap and are clearly practice changing,” agreed Nancy K. Sweitzer, MD, PhD, University of Arizona Sarver Heart Center, Tucson, as an invited discussant following Dr. Voors’ presentation. “Few therapies have been shown to impact the course of those hospitalized with acute decompensated heart failure.”
Of note in the trial, Dr. Sweitzer continued, patients were started on empagliflozin regardless of any drug therapy they might already be on for chronic HF. “Because patients in the EMPULSE trial could be enrolled with a new diagnosis of heart failure, they were, by definition, not all on chronic guideline-directed heart failure therapy. Nevertheless, such patients benefited equally from the study intervention,” she said.
“This is crucial, as it tells us these drugs have immediate and important effects and should not be withheld while other drug classes are initiated and optimized.”
EMPULSE entered patients hospitalized for acute HF, which could be de novo or a decompensation of chronic HF, without regard to ejection fraction or whether they had diabetes, and who were clinically stable after at least one dose of loop diuretics. Their ejection fractions averaged 35% and exceeded 40% in about one-third of the total cohort.
At 90 days in the win ratio analysis, the 265 patients assigned to empagliflozin 10 mg once daily were the “winners”; that is, they were more likely to show a clinical benefit about 54% of the time in paired match-ups of patient outcomes, compared with about 40% for the 265 in the control group. The match-ups were a tie 6.4% of the time.
The empagliflozin group also benefited significantly for the endpoint of death from any cause or first HF event, with a hazard ratio of 0.65 (95% CI, 0.43-0.99; P = .042). They also were less likely to experience acute renal failure (7.7% vs. 12.1% for the control group) or serious adverse events (32.3% vs. 43.6%), Dr. Voors reported.
Tempting as it might be, the findings can’t necessarily be generalized to other SGLT2 inhibitors without an evidence base. But as Dr. Voors observed, several ongoing trials are exploring dapagliflozin (Farxiga) in a similar clinical setting.
They include DICTATE-AHF in patients with diabetes admitted with acute HF, and DAPA ACT HF-TIMI 68, which is entering patients stabilized during hospitalization with acute decompensated HFrEF. The trials are scheduled for completion in 2022 and 2023, respectively.
EMPULSE was supported by the Boehringer Ingelheim–Eli Lilly Diabetes Alliance. Dr. Voors disclosed research support and consulting for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Myokardia, Novo Nordisk, Novartis, and Roche Diagnostics. Dr. Sweitzer disclosed honoraria from Acorda and Myokardia, and reported receiving research support from Novartis and Merck. Dr. Fonarow cited honoraria from Abbott, Amgen, Janssen, Medtronic, Bayer, Merck, AstraZeneca, Cytokinetics, and Novartis.
A version of this article first appeared on Medscape.com.
The sodium-glucose transporter 2 inhibitors, relative newcomers among first-line agents for chronic heart failure (HF), could well attain the same go-to status in patients hospitalized with acute HF if the EMPULSE trial has anything to say about it.
Of the study’s 530 such patients, those started on daily empagliflozin (Jardiance) soon after they were stabilized, compared with a control group, were less likely to die or be rehospitalized for HF over the next 3 months.
Also, “we saw an improvement in quality of life, we saw a greater reduction in body weight, and we didn’t see any safety concerns in this very vulnerable and sick patient population,” Adriaan A. Voors, MD, University Medical Center Groningen (the Netherlands), said when presenting the trial at the American Heart Association scientific sessions.
Patients assigned to empagliflozin had a 36% greater likelihood of showing a benefit as reflected in the treatment’s win ratio when opposed by placebo, an emerging way to express outcomes in cardiovascular clinical trials. The SGLT2 inhibitor’s win ratio for the primary endpoint was 1.36 (95% confidence interval, 1.09-1.68, P = .0054), Dr. Voors reported. The outcome consisted of death, number of HF events, time to first HF event, and 90-day change in quality of life scores.
There is reluctance in practice to start patients that early after decompensation on drugs used in chronic HF, Dr. Voors said in an interview. Empagliflozin in the trial was initiated in the stabilized setting an average of 3 days after hospital admission, he said. The trial should reassure physicians that the drug “is not only safe to start early in hospital, but it’s also beneficial to start early in hospital.”
EMPULSE, combined with support from other recent trials, “should be clinical practice changing, with early in-hospital initiation of SGLT2 inhibitors in patients hospitalized with HF being the expectation, along with clear recognition that delaying SGLT2 inhibitor initiation may expose patients to unnecessary harms and delays in improved health status,” Gregg C. Fonarow, MD, University of California Los Angeles Medical Center, told this news organization.
“For patients with HF, irrespective of ejection fraction, early in-hospital initiation of SGLT2 inhibitors – once stabilized and in the absence of contraindications – should be considered a new standard of care,” said Fonarow, who was not part of EMPULSE.
The trial also lends new weight to the strategy of “simultaneous or rapid-sequence initiation” of the so-called four pillars of guideline-directed medical therapy of HF with reduced ejection fraction in patients hospitalized with HFrEF, once they are stabilized, Dr. Fonarow said. The four-pronged approach, he noted, consists of sacubitril/valsartan (Entresto), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor.
Indeed, the new findings “fill an important gap and are clearly practice changing,” agreed Nancy K. Sweitzer, MD, PhD, University of Arizona Sarver Heart Center, Tucson, as an invited discussant following Dr. Voors’ presentation. “Few therapies have been shown to impact the course of those hospitalized with acute decompensated heart failure.”
Of note in the trial, Dr. Sweitzer continued, patients were started on empagliflozin regardless of any drug therapy they might already be on for chronic HF. “Because patients in the EMPULSE trial could be enrolled with a new diagnosis of heart failure, they were, by definition, not all on chronic guideline-directed heart failure therapy. Nevertheless, such patients benefited equally from the study intervention,” she said.
“This is crucial, as it tells us these drugs have immediate and important effects and should not be withheld while other drug classes are initiated and optimized.”
EMPULSE entered patients hospitalized for acute HF, which could be de novo or a decompensation of chronic HF, without regard to ejection fraction or whether they had diabetes, and who were clinically stable after at least one dose of loop diuretics. Their ejection fractions averaged 35% and exceeded 40% in about one-third of the total cohort.
At 90 days in the win ratio analysis, the 265 patients assigned to empagliflozin 10 mg once daily were the “winners”; that is, they were more likely to show a clinical benefit about 54% of the time in paired match-ups of patient outcomes, compared with about 40% for the 265 in the control group. The match-ups were a tie 6.4% of the time.
The empagliflozin group also benefited significantly for the endpoint of death from any cause or first HF event, with a hazard ratio of 0.65 (95% CI, 0.43-0.99; P = .042). They also were less likely to experience acute renal failure (7.7% vs. 12.1% for the control group) or serious adverse events (32.3% vs. 43.6%), Dr. Voors reported.
Tempting as it might be, the findings can’t necessarily be generalized to other SGLT2 inhibitors without an evidence base. But as Dr. Voors observed, several ongoing trials are exploring dapagliflozin (Farxiga) in a similar clinical setting.
They include DICTATE-AHF in patients with diabetes admitted with acute HF, and DAPA ACT HF-TIMI 68, which is entering patients stabilized during hospitalization with acute decompensated HFrEF. The trials are scheduled for completion in 2022 and 2023, respectively.
EMPULSE was supported by the Boehringer Ingelheim–Eli Lilly Diabetes Alliance. Dr. Voors disclosed research support and consulting for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Myokardia, Novo Nordisk, Novartis, and Roche Diagnostics. Dr. Sweitzer disclosed honoraria from Acorda and Myokardia, and reported receiving research support from Novartis and Merck. Dr. Fonarow cited honoraria from Abbott, Amgen, Janssen, Medtronic, Bayer, Merck, AstraZeneca, Cytokinetics, and Novartis.
A version of this article first appeared on Medscape.com.
FROM AHA 2021
Specific blood pressure-lowering drugs prevent onset of new diabetes
results from a new meta-analysis show.
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) – so-called renin-angiotensin system (RAS) blockers – showed the strongest association with preventive effects, while conversely, beta-blocker and thiazide diuretic antihypertensives were linked to an increased risk of new-onset diabetes.
“This study suggests that blood pressure lowering can help prevent diabetes in addition to its well-established beneficial effects in reducing cardiovascular events,” write Milad Nazarzadeh and colleagues with the Blood Pressure Lowering Treatment Trialists’ Collaboration in their article published in The Lancet.
“The differing effects of the drug classes support decision-making for antihypertensive drug choice according to an individual’s risk profile,” note Mr. Nazarzadeh, of Deep Medicine, Oxford Martin School, University of Oxford, U.K., and colleagues.
“In particular, [RAS inhibitors], ACE inhibitors and ARBs, should become the drugs of choice when clinical risk of diabetes is of concern, whereas beta blockers and thiazide diuretics should be avoided where possible,” they add.
In an accompanying editorial, Matthew A. Cavender, MD, MPH, and Robert C. Wirka, MD, of the University of North Carolina at Chapel Hill, agree that the new findings, along with the bulk of previous evidence, point to an important role of RAS-inhibiting drugs in diabetes prevention.
“Based on the accumulated evidence, including the results of these analyses, blood pressure control, particularly with RAS inhibition, should be considered as a possible strategy to reduce the risk of developing diabetes,” they write.
They note that, while “the absolute risk reduction found in this meta-analysis is modest, interventions with small benefits can have an outsized effect when applied to conditions as common as hypertension.”
And commenting on the findings to the U.K. Science & Media Centre, Marc George, MBChB, PhD, blood pressure clinical lead for University College London Hospital, U.K., said: “Lowering blood pressure prevents heart attacks, strokes, and kidney failure, and this new large and comprehensive study published in The Lancet also shows that it lowers the risk of developing diabetes. Until now this effect was not clear.”
Kevin McConway, PhD, emeritus professor of applied statistics, The Open University, U.K., similarly concurs: “Though there is good evidence that lowering people’s blood pressure, if it is too high, can have important health benefits in reducing the risk of heart attacks and strokes, it hasn’t been clear whether lowering blood pressure can reduce the chance of developing type 2 diabetes in the future. This is an impressive study.”
RAS blockers associated with lower diabetes risk
The findings are from an individual data meta-analysis of 19 randomized, placebo-controlled trials conducted between 1973 and 2008 and involving five major classes of antihypertensive drugs: ACE inhibitors, ARBs, beta-blockers, thiazide diuretics, and calcium channel blockers.
Overall, the studies included 145,939 participants, of whom 60.6% were men.
Over a median follow-up of 4.5 years, 9,883 of the study participants developed new-onset type 2 diabetes.
Those treated with ACE inhibitors or ARBs had a reduced relative risk of new-onset diabetes that was nearly identical (risk reduction, 0.84 for both) versus placebo.
However, treatment with beta-blockers or thiazide diuretics was associated with an increased risk of type 2 diabetes (RR, 1.48 and 1.20, respectively), consistent with previous evidence that, specifically, second-line thiazide diuretics and third-line beta blockers increase the risk of diabetes.
No significant reduction or increase in risk was observed with calcium channel blockers (RR, 1.02).
For the reductions with ACE inhibitors and ARBs, each reduction in systolic blood pressure of 5-mm Hg was associated with an 11% reduced risk of developing diabetes.
“The relative magnitude of reduction per 5-mm Hg systolic blood pressure lowering was similar to those reported for prevention of major cardiovascular events,” the authors say.
“[This] will strengthen the case for blood pressure reduction through lifestyle interventions known to reduce blood pressure, and blood pressure lowering treatments with drugs, and possibly device therapies,” they say.
In the opposite direction, research has suggested that each 20-mm Hg increase in systolic blood pressure is associated with as much as a 77% increased risk of type 2 diabetes; however, the causality of that association is uncertain, the authors note.
Results fill gap in evidence for guidelines
The meta-analysis findings were further validated in a supplemental mendelian randomization analysis, which used data from the International Consortium for Blood Pressure genome-wide association study and the UK Biobank. The analysis showed that people with genetic variants that have a similar effect on the RAS pathway as ACE inhibitors and ARBs also had a reduced risk of diabetes.
On this point, Dipender Gill, BMBCh, PhD, lecturer in clinical pharmacology and therapeutics at St. George’s, University of London, told the U.K. Science and Media Centre: “This is a comprehensive study triangulating clinical trial and genetic data to find support for effects of blood pressure reduction through particular pharmacological targets on glycemic control and risk of type 2 diabetes.”
Mr. Nazarzadeh and colleagues say that uncertainty regarding whether the reduction in diabetes risk is caused by blood pressure lowering itself, or by some other effect of the antihypertensive drugs, has meant that guideline recommendations on the role of antihypertensive drugs have been lacking.
However, the authors assert that “our study fills this gap in evidence using individual participant data from randomized controlled trials and assessing effects for a standardized fixed degree of blood pressure reduction.”
“With consistent results from both randomized controlled trials and genetic analyses, we have shown that elevated blood pressure is indeed a modifiable risk factor for new-onset type 2 diabetes in people without a diagnosis of diabetes, with a relative effect size similar to those seen for the prevention of major cardiovascular disease,” they state.
Authors of U.S. hypertension guidelines should follow lead of ESC
Under the European Society of Cardiology (ESC) guidelines, RAS inhibitors (in combination with a calcium channel blocker or thiazide diuretic) have a class 1 recommendation for the treatment of hypertension; however, diabetes and cardiology societies in the United States only recommend a preference for a RAS inhibitor over other agents among those with concomitant albuminuria.
But with an estimated 13% of Americans having diabetes and a striking 34.5% having prediabetes, the need for more measures to tackle the problem is urgent, say Dr. Cavender and Dr. Wirka in their editorial.
“Perhaps these data are enough to encourage the writers of the hypertension guidelines in the U.S. to follow the lead of the ESC to make RAS inhibitors the first-line hypertension treatment for all patients and not just in those with albuminuria,” they state.
Dr. Cavender has reported receiving research support from Amgen, AstraZeneca, Boehringer-Ingelheim, CSL Behring, and Novartis, and consulting fees from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Boston Scientific, Edwards Lifesciences, Merck, and Novo Nordisk. Disclosures for the other authors are listed with the article. Dr. Wirka and Dr. George have reported no relevant financial relationships. Dr. McConway is a trustee of the SMC and member of its advisory committee. Dr. Gill is employed part-time by Novo Nordisk.
A version of this article first appeared on Medscape.com.
results from a new meta-analysis show.
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) – so-called renin-angiotensin system (RAS) blockers – showed the strongest association with preventive effects, while conversely, beta-blocker and thiazide diuretic antihypertensives were linked to an increased risk of new-onset diabetes.
“This study suggests that blood pressure lowering can help prevent diabetes in addition to its well-established beneficial effects in reducing cardiovascular events,” write Milad Nazarzadeh and colleagues with the Blood Pressure Lowering Treatment Trialists’ Collaboration in their article published in The Lancet.
“The differing effects of the drug classes support decision-making for antihypertensive drug choice according to an individual’s risk profile,” note Mr. Nazarzadeh, of Deep Medicine, Oxford Martin School, University of Oxford, U.K., and colleagues.
“In particular, [RAS inhibitors], ACE inhibitors and ARBs, should become the drugs of choice when clinical risk of diabetes is of concern, whereas beta blockers and thiazide diuretics should be avoided where possible,” they add.
In an accompanying editorial, Matthew A. Cavender, MD, MPH, and Robert C. Wirka, MD, of the University of North Carolina at Chapel Hill, agree that the new findings, along with the bulk of previous evidence, point to an important role of RAS-inhibiting drugs in diabetes prevention.
“Based on the accumulated evidence, including the results of these analyses, blood pressure control, particularly with RAS inhibition, should be considered as a possible strategy to reduce the risk of developing diabetes,” they write.
They note that, while “the absolute risk reduction found in this meta-analysis is modest, interventions with small benefits can have an outsized effect when applied to conditions as common as hypertension.”
And commenting on the findings to the U.K. Science & Media Centre, Marc George, MBChB, PhD, blood pressure clinical lead for University College London Hospital, U.K., said: “Lowering blood pressure prevents heart attacks, strokes, and kidney failure, and this new large and comprehensive study published in The Lancet also shows that it lowers the risk of developing diabetes. Until now this effect was not clear.”
Kevin McConway, PhD, emeritus professor of applied statistics, The Open University, U.K., similarly concurs: “Though there is good evidence that lowering people’s blood pressure, if it is too high, can have important health benefits in reducing the risk of heart attacks and strokes, it hasn’t been clear whether lowering blood pressure can reduce the chance of developing type 2 diabetes in the future. This is an impressive study.”
RAS blockers associated with lower diabetes risk
The findings are from an individual data meta-analysis of 19 randomized, placebo-controlled trials conducted between 1973 and 2008 and involving five major classes of antihypertensive drugs: ACE inhibitors, ARBs, beta-blockers, thiazide diuretics, and calcium channel blockers.
Overall, the studies included 145,939 participants, of whom 60.6% were men.
Over a median follow-up of 4.5 years, 9,883 of the study participants developed new-onset type 2 diabetes.
Those treated with ACE inhibitors or ARBs had a reduced relative risk of new-onset diabetes that was nearly identical (risk reduction, 0.84 for both) versus placebo.
However, treatment with beta-blockers or thiazide diuretics was associated with an increased risk of type 2 diabetes (RR, 1.48 and 1.20, respectively), consistent with previous evidence that, specifically, second-line thiazide diuretics and third-line beta blockers increase the risk of diabetes.
No significant reduction or increase in risk was observed with calcium channel blockers (RR, 1.02).
For the reductions with ACE inhibitors and ARBs, each reduction in systolic blood pressure of 5-mm Hg was associated with an 11% reduced risk of developing diabetes.
“The relative magnitude of reduction per 5-mm Hg systolic blood pressure lowering was similar to those reported for prevention of major cardiovascular events,” the authors say.
“[This] will strengthen the case for blood pressure reduction through lifestyle interventions known to reduce blood pressure, and blood pressure lowering treatments with drugs, and possibly device therapies,” they say.
In the opposite direction, research has suggested that each 20-mm Hg increase in systolic blood pressure is associated with as much as a 77% increased risk of type 2 diabetes; however, the causality of that association is uncertain, the authors note.
Results fill gap in evidence for guidelines
The meta-analysis findings were further validated in a supplemental mendelian randomization analysis, which used data from the International Consortium for Blood Pressure genome-wide association study and the UK Biobank. The analysis showed that people with genetic variants that have a similar effect on the RAS pathway as ACE inhibitors and ARBs also had a reduced risk of diabetes.
On this point, Dipender Gill, BMBCh, PhD, lecturer in clinical pharmacology and therapeutics at St. George’s, University of London, told the U.K. Science and Media Centre: “This is a comprehensive study triangulating clinical trial and genetic data to find support for effects of blood pressure reduction through particular pharmacological targets on glycemic control and risk of type 2 diabetes.”
Mr. Nazarzadeh and colleagues say that uncertainty regarding whether the reduction in diabetes risk is caused by blood pressure lowering itself, or by some other effect of the antihypertensive drugs, has meant that guideline recommendations on the role of antihypertensive drugs have been lacking.
However, the authors assert that “our study fills this gap in evidence using individual participant data from randomized controlled trials and assessing effects for a standardized fixed degree of blood pressure reduction.”
“With consistent results from both randomized controlled trials and genetic analyses, we have shown that elevated blood pressure is indeed a modifiable risk factor for new-onset type 2 diabetes in people without a diagnosis of diabetes, with a relative effect size similar to those seen for the prevention of major cardiovascular disease,” they state.
Authors of U.S. hypertension guidelines should follow lead of ESC
Under the European Society of Cardiology (ESC) guidelines, RAS inhibitors (in combination with a calcium channel blocker or thiazide diuretic) have a class 1 recommendation for the treatment of hypertension; however, diabetes and cardiology societies in the United States only recommend a preference for a RAS inhibitor over other agents among those with concomitant albuminuria.
But with an estimated 13% of Americans having diabetes and a striking 34.5% having prediabetes, the need for more measures to tackle the problem is urgent, say Dr. Cavender and Dr. Wirka in their editorial.
“Perhaps these data are enough to encourage the writers of the hypertension guidelines in the U.S. to follow the lead of the ESC to make RAS inhibitors the first-line hypertension treatment for all patients and not just in those with albuminuria,” they state.
Dr. Cavender has reported receiving research support from Amgen, AstraZeneca, Boehringer-Ingelheim, CSL Behring, and Novartis, and consulting fees from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Boston Scientific, Edwards Lifesciences, Merck, and Novo Nordisk. Disclosures for the other authors are listed with the article. Dr. Wirka and Dr. George have reported no relevant financial relationships. Dr. McConway is a trustee of the SMC and member of its advisory committee. Dr. Gill is employed part-time by Novo Nordisk.
A version of this article first appeared on Medscape.com.
results from a new meta-analysis show.
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) – so-called renin-angiotensin system (RAS) blockers – showed the strongest association with preventive effects, while conversely, beta-blocker and thiazide diuretic antihypertensives were linked to an increased risk of new-onset diabetes.
“This study suggests that blood pressure lowering can help prevent diabetes in addition to its well-established beneficial effects in reducing cardiovascular events,” write Milad Nazarzadeh and colleagues with the Blood Pressure Lowering Treatment Trialists’ Collaboration in their article published in The Lancet.
“The differing effects of the drug classes support decision-making for antihypertensive drug choice according to an individual’s risk profile,” note Mr. Nazarzadeh, of Deep Medicine, Oxford Martin School, University of Oxford, U.K., and colleagues.
“In particular, [RAS inhibitors], ACE inhibitors and ARBs, should become the drugs of choice when clinical risk of diabetes is of concern, whereas beta blockers and thiazide diuretics should be avoided where possible,” they add.
In an accompanying editorial, Matthew A. Cavender, MD, MPH, and Robert C. Wirka, MD, of the University of North Carolina at Chapel Hill, agree that the new findings, along with the bulk of previous evidence, point to an important role of RAS-inhibiting drugs in diabetes prevention.
“Based on the accumulated evidence, including the results of these analyses, blood pressure control, particularly with RAS inhibition, should be considered as a possible strategy to reduce the risk of developing diabetes,” they write.
They note that, while “the absolute risk reduction found in this meta-analysis is modest, interventions with small benefits can have an outsized effect when applied to conditions as common as hypertension.”
And commenting on the findings to the U.K. Science & Media Centre, Marc George, MBChB, PhD, blood pressure clinical lead for University College London Hospital, U.K., said: “Lowering blood pressure prevents heart attacks, strokes, and kidney failure, and this new large and comprehensive study published in The Lancet also shows that it lowers the risk of developing diabetes. Until now this effect was not clear.”
Kevin McConway, PhD, emeritus professor of applied statistics, The Open University, U.K., similarly concurs: “Though there is good evidence that lowering people’s blood pressure, if it is too high, can have important health benefits in reducing the risk of heart attacks and strokes, it hasn’t been clear whether lowering blood pressure can reduce the chance of developing type 2 diabetes in the future. This is an impressive study.”
RAS blockers associated with lower diabetes risk
The findings are from an individual data meta-analysis of 19 randomized, placebo-controlled trials conducted between 1973 and 2008 and involving five major classes of antihypertensive drugs: ACE inhibitors, ARBs, beta-blockers, thiazide diuretics, and calcium channel blockers.
Overall, the studies included 145,939 participants, of whom 60.6% were men.
Over a median follow-up of 4.5 years, 9,883 of the study participants developed new-onset type 2 diabetes.
Those treated with ACE inhibitors or ARBs had a reduced relative risk of new-onset diabetes that was nearly identical (risk reduction, 0.84 for both) versus placebo.
However, treatment with beta-blockers or thiazide diuretics was associated with an increased risk of type 2 diabetes (RR, 1.48 and 1.20, respectively), consistent with previous evidence that, specifically, second-line thiazide diuretics and third-line beta blockers increase the risk of diabetes.
No significant reduction or increase in risk was observed with calcium channel blockers (RR, 1.02).
For the reductions with ACE inhibitors and ARBs, each reduction in systolic blood pressure of 5-mm Hg was associated with an 11% reduced risk of developing diabetes.
“The relative magnitude of reduction per 5-mm Hg systolic blood pressure lowering was similar to those reported for prevention of major cardiovascular events,” the authors say.
“[This] will strengthen the case for blood pressure reduction through lifestyle interventions known to reduce blood pressure, and blood pressure lowering treatments with drugs, and possibly device therapies,” they say.
In the opposite direction, research has suggested that each 20-mm Hg increase in systolic blood pressure is associated with as much as a 77% increased risk of type 2 diabetes; however, the causality of that association is uncertain, the authors note.
Results fill gap in evidence for guidelines
The meta-analysis findings were further validated in a supplemental mendelian randomization analysis, which used data from the International Consortium for Blood Pressure genome-wide association study and the UK Biobank. The analysis showed that people with genetic variants that have a similar effect on the RAS pathway as ACE inhibitors and ARBs also had a reduced risk of diabetes.
On this point, Dipender Gill, BMBCh, PhD, lecturer in clinical pharmacology and therapeutics at St. George’s, University of London, told the U.K. Science and Media Centre: “This is a comprehensive study triangulating clinical trial and genetic data to find support for effects of blood pressure reduction through particular pharmacological targets on glycemic control and risk of type 2 diabetes.”
Mr. Nazarzadeh and colleagues say that uncertainty regarding whether the reduction in diabetes risk is caused by blood pressure lowering itself, or by some other effect of the antihypertensive drugs, has meant that guideline recommendations on the role of antihypertensive drugs have been lacking.
However, the authors assert that “our study fills this gap in evidence using individual participant data from randomized controlled trials and assessing effects for a standardized fixed degree of blood pressure reduction.”
“With consistent results from both randomized controlled trials and genetic analyses, we have shown that elevated blood pressure is indeed a modifiable risk factor for new-onset type 2 diabetes in people without a diagnosis of diabetes, with a relative effect size similar to those seen for the prevention of major cardiovascular disease,” they state.
Authors of U.S. hypertension guidelines should follow lead of ESC
Under the European Society of Cardiology (ESC) guidelines, RAS inhibitors (in combination with a calcium channel blocker or thiazide diuretic) have a class 1 recommendation for the treatment of hypertension; however, diabetes and cardiology societies in the United States only recommend a preference for a RAS inhibitor over other agents among those with concomitant albuminuria.
But with an estimated 13% of Americans having diabetes and a striking 34.5% having prediabetes, the need for more measures to tackle the problem is urgent, say Dr. Cavender and Dr. Wirka in their editorial.
“Perhaps these data are enough to encourage the writers of the hypertension guidelines in the U.S. to follow the lead of the ESC to make RAS inhibitors the first-line hypertension treatment for all patients and not just in those with albuminuria,” they state.
Dr. Cavender has reported receiving research support from Amgen, AstraZeneca, Boehringer-Ingelheim, CSL Behring, and Novartis, and consulting fees from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Boston Scientific, Edwards Lifesciences, Merck, and Novo Nordisk. Disclosures for the other authors are listed with the article. Dr. Wirka and Dr. George have reported no relevant financial relationships. Dr. McConway is a trustee of the SMC and member of its advisory committee. Dr. Gill is employed part-time by Novo Nordisk.
A version of this article first appeared on Medscape.com.
FROM THE LANCET
Tofacitinib postmarketing trial data shed light on JAK inhibitor risks
Additional analyses of a postmarketing trial that was required after the Food and Drug Administration’s approval of the Janus kinase inhibitor tofacitinib (Xeljanz, Xeljanz XR) has identified characteristics of older patients with rheumatoid arthritis with at least one cardiovascular risk factor who may be at higher risk for major adverse cardiovascular events (MACE) when taking the drug.
Results from the phase 3b/4 ORAL Surveillance trial presented at the virtual annual meeting of the American College of Rheumatology show that people taking tofacitinib for RA with at least one cardiovascular (CV) risk factor had a nonsignificant higher risk for MACE than did people taking tumor necrosis factor inhibitors (TNFi), with the risk from tofacitinib more pronounced in current smokers, aspirin users, people older than 65 years, and men, compared with women.
“It is the first large, randomized safety study of active RA patients with increased CV risk comparing tofacitinib to TNF inhibition,” study author Christina Charles-Schoeman, MD, said in an interview. “These data emphasize the importance of assessing baseline CV risk when treating patients with RA.” Dr. Charles-Schoeman is chief of rheumatology at the University of California, Los Angeles.
The results shed further light on the trial’s findings, which the FDA used in September 2021 to mandate boxed warnings about the risk of MI or stroke, cancer, venous thromboembolism, and death, as well as updated indications, for tofacitinib and other JAK inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq). The FDA limited all approved uses of these three medications to patients who have not responded well to TNFi to ensure their benefits outweigh their risks.
Tofacitinib is indicated for RA, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis. Baricitinib and upadacitinib are approved only for RA.
While the overall results of the trial results show nonsignificant increased incidence rates for MACE in tofacitinib users versus TNFI users, Katherine Liao, MD, a rheumatologist at Brigham and Women’s Hospital in Boston, noted that more information is needed to determine who is at greatest risk. “Another thing to keep in mind is, while there was evidence of an elevated relative risk for MACE, compared to TNFi, the absolute risk, based on the numbers what we know so far, is small,” she said.
The trial compared two different doses of tofacitinib – 5 mg (1,455 patients) and 10 mg (n = 1,456) twice daily – and TNFi (n = 1,451) in people with moderate to severe RA over age 50. Patient characteristics were similar across all three treatment arms, Dr. Charles-Schoeman said. All patients had inadequate response to methotrexate, and about 57% in all three treatment groups were taking corticosteroids. The 10-mg tofacitinib patients switched to the 5-mg dose in February 2019 but represent the 10-mg group in the study analysis.
ORAL Surveillance demonstrated a 24% greater risk of MACE in the 5-mg tofacitinib patients and a 43% heightened risk the 10-mg group, compared with patients who received a TNFi.
The differentiating factor for MACE incidence was MI. The higher- and lower-dose tofacitinib groups had 69% and 80% greater risk for MI. While the risk for fatal MI were similar across all three treatment groups, the risk for nonfatal MI were more than doubled in the respective tofacitinib groups: hazard ratios of 2.32 and 2.08. The incidence of stroke was similar across all three arms, Dr. Charles-Schoeman said.
The study identified a number of baseline characteristics as independent overall risk factors for MACE across all treatment groups. Current smoking and aspirin use more than doubled the risk (HR, 2.18; P < .0001 and HR, 2.11; P = .004, respectively), while age greater than 65 years and male sex approached that level (HR, 1.81; P = .0011 and HR, 1.81; P = .0015) approached that level. Other factors that elevated the risk of MACE to a lesser extent were a history of diabetes, hypertension or coronary artery procedures, and a total cholesterol to HDL ratio greater than4.
Other ORAL Surveillance subanalyses and tofacitinib real-world data reported
This was one of several analyses presented at ACR 2021 that compared adverse event risks for tofacitinib versus TNFi drugs. A separate analysis of claims data from patients with RA in two U.S. insurance databases plus Medicare found a statistically nonsignificant increased risk of adverse CV outcomes (MI or stroke) with tofacitinib, compared with TNFi users, among patients who met the same inclusion and exclusion criteria of the ORAL Surveillance trial but not in a “real-world evidence” cohort of more than 102,000 patients with RA in routine care from the databases.
Two additional ORAL Surveillance analyses presented at ACR 2021 gave details about risk factors for higher rates of malignancies and venous thromboembolic events found in patients taking tofacitinib with at least one CV risk factor. As would be expected, older age (≥65 vs. 50-64 years) and current or past smoking (vs. never smoking) were independent risk factors for higher malignancy rates across all treatment arms. Pulmonary embolism events across treatment groups were independently associated with a history of venous thromboembolism, baseline use of oral contraceptives or hormone replacement therapy, baseline body mass index of at least 30 kg/m2, age 65 or older, and history of hypertension.
The ORAL Surveillance findings are worth considering when determining treatments for RA patients with CV risk factors, Dr. Charles-Schoeman said. “Tofacitinib remains an effective RA treatment,” she said. “The choice of specific RA treatment for any patient remains an individual decision between the patient and physician, which is decided based on a number of different factors. This new study provides additional information regarding both tofacitinib as well as traditional CV risk factors for discussion with the patient.”
The ORAL Surveillance results may give rheumatologists reason to rethink use of tofacitinib in some patients with CV risk, said Dr. Liao of Brigham and Women’s Hospital in Boston. “Currently, we have limited data and are still awaiting a report of the full trial results,” she said in an interview. “Based on the data available, I can think of a few patients in my clinic where I would reconsider use of these drugs, i.e., history of heart attack with stable angina, especially if there are other options.” However, she noted that many patients on tofacitinib have already failed on older treatments.
These data emphasize the importance of addressing CV risk with patients, said Brittany N. Weber, MD, PhD, a cardio-rheumatologist at Brigham and Women’s Hospital who works with Dr. Liao. “It is also an opportunity to discuss modification of risk factors and to discuss primary prevention therapies, such as statin therapy, where appropriate,” she added. “Based on the individual’s cardiovascular risk, there may be a role for further risk stratification to further understand an individual’s risk, which can also inform primary prevention cardiovascular therapies and help guide these discussions.” Risk stratification could include cardiac CT for calcium scoring or cardiac coronary CT angiography for determining atherosclerotic burden.
The study was sponsored by Pfizer. Dr. Charles-Schoeman disclosed relationships with AbbVie, Bristol-Myers Squibb, Gilead Sciences, Pfizer, and Regeneron-Sanofi. Dr. Liao and Dr. Weber have no relevant disclosures.
Additional analyses of a postmarketing trial that was required after the Food and Drug Administration’s approval of the Janus kinase inhibitor tofacitinib (Xeljanz, Xeljanz XR) has identified characteristics of older patients with rheumatoid arthritis with at least one cardiovascular risk factor who may be at higher risk for major adverse cardiovascular events (MACE) when taking the drug.
Results from the phase 3b/4 ORAL Surveillance trial presented at the virtual annual meeting of the American College of Rheumatology show that people taking tofacitinib for RA with at least one cardiovascular (CV) risk factor had a nonsignificant higher risk for MACE than did people taking tumor necrosis factor inhibitors (TNFi), with the risk from tofacitinib more pronounced in current smokers, aspirin users, people older than 65 years, and men, compared with women.
“It is the first large, randomized safety study of active RA patients with increased CV risk comparing tofacitinib to TNF inhibition,” study author Christina Charles-Schoeman, MD, said in an interview. “These data emphasize the importance of assessing baseline CV risk when treating patients with RA.” Dr. Charles-Schoeman is chief of rheumatology at the University of California, Los Angeles.
The results shed further light on the trial’s findings, which the FDA used in September 2021 to mandate boxed warnings about the risk of MI or stroke, cancer, venous thromboembolism, and death, as well as updated indications, for tofacitinib and other JAK inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq). The FDA limited all approved uses of these three medications to patients who have not responded well to TNFi to ensure their benefits outweigh their risks.
Tofacitinib is indicated for RA, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis. Baricitinib and upadacitinib are approved only for RA.
While the overall results of the trial results show nonsignificant increased incidence rates for MACE in tofacitinib users versus TNFI users, Katherine Liao, MD, a rheumatologist at Brigham and Women’s Hospital in Boston, noted that more information is needed to determine who is at greatest risk. “Another thing to keep in mind is, while there was evidence of an elevated relative risk for MACE, compared to TNFi, the absolute risk, based on the numbers what we know so far, is small,” she said.
The trial compared two different doses of tofacitinib – 5 mg (1,455 patients) and 10 mg (n = 1,456) twice daily – and TNFi (n = 1,451) in people with moderate to severe RA over age 50. Patient characteristics were similar across all three treatment arms, Dr. Charles-Schoeman said. All patients had inadequate response to methotrexate, and about 57% in all three treatment groups were taking corticosteroids. The 10-mg tofacitinib patients switched to the 5-mg dose in February 2019 but represent the 10-mg group in the study analysis.
ORAL Surveillance demonstrated a 24% greater risk of MACE in the 5-mg tofacitinib patients and a 43% heightened risk the 10-mg group, compared with patients who received a TNFi.
The differentiating factor for MACE incidence was MI. The higher- and lower-dose tofacitinib groups had 69% and 80% greater risk for MI. While the risk for fatal MI were similar across all three treatment groups, the risk for nonfatal MI were more than doubled in the respective tofacitinib groups: hazard ratios of 2.32 and 2.08. The incidence of stroke was similar across all three arms, Dr. Charles-Schoeman said.
The study identified a number of baseline characteristics as independent overall risk factors for MACE across all treatment groups. Current smoking and aspirin use more than doubled the risk (HR, 2.18; P < .0001 and HR, 2.11; P = .004, respectively), while age greater than 65 years and male sex approached that level (HR, 1.81; P = .0011 and HR, 1.81; P = .0015) approached that level. Other factors that elevated the risk of MACE to a lesser extent were a history of diabetes, hypertension or coronary artery procedures, and a total cholesterol to HDL ratio greater than4.
Other ORAL Surveillance subanalyses and tofacitinib real-world data reported
This was one of several analyses presented at ACR 2021 that compared adverse event risks for tofacitinib versus TNFi drugs. A separate analysis of claims data from patients with RA in two U.S. insurance databases plus Medicare found a statistically nonsignificant increased risk of adverse CV outcomes (MI or stroke) with tofacitinib, compared with TNFi users, among patients who met the same inclusion and exclusion criteria of the ORAL Surveillance trial but not in a “real-world evidence” cohort of more than 102,000 patients with RA in routine care from the databases.
Two additional ORAL Surveillance analyses presented at ACR 2021 gave details about risk factors for higher rates of malignancies and venous thromboembolic events found in patients taking tofacitinib with at least one CV risk factor. As would be expected, older age (≥65 vs. 50-64 years) and current or past smoking (vs. never smoking) were independent risk factors for higher malignancy rates across all treatment arms. Pulmonary embolism events across treatment groups were independently associated with a history of venous thromboembolism, baseline use of oral contraceptives or hormone replacement therapy, baseline body mass index of at least 30 kg/m2, age 65 or older, and history of hypertension.
The ORAL Surveillance findings are worth considering when determining treatments for RA patients with CV risk factors, Dr. Charles-Schoeman said. “Tofacitinib remains an effective RA treatment,” she said. “The choice of specific RA treatment for any patient remains an individual decision between the patient and physician, which is decided based on a number of different factors. This new study provides additional information regarding both tofacitinib as well as traditional CV risk factors for discussion with the patient.”
The ORAL Surveillance results may give rheumatologists reason to rethink use of tofacitinib in some patients with CV risk, said Dr. Liao of Brigham and Women’s Hospital in Boston. “Currently, we have limited data and are still awaiting a report of the full trial results,” she said in an interview. “Based on the data available, I can think of a few patients in my clinic where I would reconsider use of these drugs, i.e., history of heart attack with stable angina, especially if there are other options.” However, she noted that many patients on tofacitinib have already failed on older treatments.
These data emphasize the importance of addressing CV risk with patients, said Brittany N. Weber, MD, PhD, a cardio-rheumatologist at Brigham and Women’s Hospital who works with Dr. Liao. “It is also an opportunity to discuss modification of risk factors and to discuss primary prevention therapies, such as statin therapy, where appropriate,” she added. “Based on the individual’s cardiovascular risk, there may be a role for further risk stratification to further understand an individual’s risk, which can also inform primary prevention cardiovascular therapies and help guide these discussions.” Risk stratification could include cardiac CT for calcium scoring or cardiac coronary CT angiography for determining atherosclerotic burden.
The study was sponsored by Pfizer. Dr. Charles-Schoeman disclosed relationships with AbbVie, Bristol-Myers Squibb, Gilead Sciences, Pfizer, and Regeneron-Sanofi. Dr. Liao and Dr. Weber have no relevant disclosures.
Additional analyses of a postmarketing trial that was required after the Food and Drug Administration’s approval of the Janus kinase inhibitor tofacitinib (Xeljanz, Xeljanz XR) has identified characteristics of older patients with rheumatoid arthritis with at least one cardiovascular risk factor who may be at higher risk for major adverse cardiovascular events (MACE) when taking the drug.
Results from the phase 3b/4 ORAL Surveillance trial presented at the virtual annual meeting of the American College of Rheumatology show that people taking tofacitinib for RA with at least one cardiovascular (CV) risk factor had a nonsignificant higher risk for MACE than did people taking tumor necrosis factor inhibitors (TNFi), with the risk from tofacitinib more pronounced in current smokers, aspirin users, people older than 65 years, and men, compared with women.
“It is the first large, randomized safety study of active RA patients with increased CV risk comparing tofacitinib to TNF inhibition,” study author Christina Charles-Schoeman, MD, said in an interview. “These data emphasize the importance of assessing baseline CV risk when treating patients with RA.” Dr. Charles-Schoeman is chief of rheumatology at the University of California, Los Angeles.
The results shed further light on the trial’s findings, which the FDA used in September 2021 to mandate boxed warnings about the risk of MI or stroke, cancer, venous thromboembolism, and death, as well as updated indications, for tofacitinib and other JAK inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq). The FDA limited all approved uses of these three medications to patients who have not responded well to TNFi to ensure their benefits outweigh their risks.
Tofacitinib is indicated for RA, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis. Baricitinib and upadacitinib are approved only for RA.
While the overall results of the trial results show nonsignificant increased incidence rates for MACE in tofacitinib users versus TNFI users, Katherine Liao, MD, a rheumatologist at Brigham and Women’s Hospital in Boston, noted that more information is needed to determine who is at greatest risk. “Another thing to keep in mind is, while there was evidence of an elevated relative risk for MACE, compared to TNFi, the absolute risk, based on the numbers what we know so far, is small,” she said.
The trial compared two different doses of tofacitinib – 5 mg (1,455 patients) and 10 mg (n = 1,456) twice daily – and TNFi (n = 1,451) in people with moderate to severe RA over age 50. Patient characteristics were similar across all three treatment arms, Dr. Charles-Schoeman said. All patients had inadequate response to methotrexate, and about 57% in all three treatment groups were taking corticosteroids. The 10-mg tofacitinib patients switched to the 5-mg dose in February 2019 but represent the 10-mg group in the study analysis.
ORAL Surveillance demonstrated a 24% greater risk of MACE in the 5-mg tofacitinib patients and a 43% heightened risk the 10-mg group, compared with patients who received a TNFi.
The differentiating factor for MACE incidence was MI. The higher- and lower-dose tofacitinib groups had 69% and 80% greater risk for MI. While the risk for fatal MI were similar across all three treatment groups, the risk for nonfatal MI were more than doubled in the respective tofacitinib groups: hazard ratios of 2.32 and 2.08. The incidence of stroke was similar across all three arms, Dr. Charles-Schoeman said.
The study identified a number of baseline characteristics as independent overall risk factors for MACE across all treatment groups. Current smoking and aspirin use more than doubled the risk (HR, 2.18; P < .0001 and HR, 2.11; P = .004, respectively), while age greater than 65 years and male sex approached that level (HR, 1.81; P = .0011 and HR, 1.81; P = .0015) approached that level. Other factors that elevated the risk of MACE to a lesser extent were a history of diabetes, hypertension or coronary artery procedures, and a total cholesterol to HDL ratio greater than4.
Other ORAL Surveillance subanalyses and tofacitinib real-world data reported
This was one of several analyses presented at ACR 2021 that compared adverse event risks for tofacitinib versus TNFi drugs. A separate analysis of claims data from patients with RA in two U.S. insurance databases plus Medicare found a statistically nonsignificant increased risk of adverse CV outcomes (MI or stroke) with tofacitinib, compared with TNFi users, among patients who met the same inclusion and exclusion criteria of the ORAL Surveillance trial but not in a “real-world evidence” cohort of more than 102,000 patients with RA in routine care from the databases.
Two additional ORAL Surveillance analyses presented at ACR 2021 gave details about risk factors for higher rates of malignancies and venous thromboembolic events found in patients taking tofacitinib with at least one CV risk factor. As would be expected, older age (≥65 vs. 50-64 years) and current or past smoking (vs. never smoking) were independent risk factors for higher malignancy rates across all treatment arms. Pulmonary embolism events across treatment groups were independently associated with a history of venous thromboembolism, baseline use of oral contraceptives or hormone replacement therapy, baseline body mass index of at least 30 kg/m2, age 65 or older, and history of hypertension.
The ORAL Surveillance findings are worth considering when determining treatments for RA patients with CV risk factors, Dr. Charles-Schoeman said. “Tofacitinib remains an effective RA treatment,” she said. “The choice of specific RA treatment for any patient remains an individual decision between the patient and physician, which is decided based on a number of different factors. This new study provides additional information regarding both tofacitinib as well as traditional CV risk factors for discussion with the patient.”
The ORAL Surveillance results may give rheumatologists reason to rethink use of tofacitinib in some patients with CV risk, said Dr. Liao of Brigham and Women’s Hospital in Boston. “Currently, we have limited data and are still awaiting a report of the full trial results,” she said in an interview. “Based on the data available, I can think of a few patients in my clinic where I would reconsider use of these drugs, i.e., history of heart attack with stable angina, especially if there are other options.” However, she noted that many patients on tofacitinib have already failed on older treatments.
These data emphasize the importance of addressing CV risk with patients, said Brittany N. Weber, MD, PhD, a cardio-rheumatologist at Brigham and Women’s Hospital who works with Dr. Liao. “It is also an opportunity to discuss modification of risk factors and to discuss primary prevention therapies, such as statin therapy, where appropriate,” she added. “Based on the individual’s cardiovascular risk, there may be a role for further risk stratification to further understand an individual’s risk, which can also inform primary prevention cardiovascular therapies and help guide these discussions.” Risk stratification could include cardiac CT for calcium scoring or cardiac coronary CT angiography for determining atherosclerotic burden.
The study was sponsored by Pfizer. Dr. Charles-Schoeman disclosed relationships with AbbVie, Bristol-Myers Squibb, Gilead Sciences, Pfizer, and Regeneron-Sanofi. Dr. Liao and Dr. Weber have no relevant disclosures.
FROM ACR 2021
More STEP data: Semaglutide cuts weight, cravings, beats liraglutide
The STEP 5 clinical trial extends favorable weight loss from 1 year out to 2 years for the glucagon-like peptide-1 (GLP-1) agonist semaglutide (Wegovy, Novo Nordisk), given as a once-weekly 2.4-mg subcutaneous injection, and some food cravings were improved in a subgroup analysis.
In another study, STEP 8, weight loss was greater at 68 weeks with semaglutide subcutaneous injection than with a 3-mg daily subcutaneous injection of another GLP-1 agonist, liraglutide (Saxenda, Novo Nordisk), approved earlier for weight loss.
Researchers presented these promising outcomes, with no new safety signals, at ObesityWeek® 2021.
However, there is more to learn about the drug class, researchers agree. Follow-up is still relatively short for a chronic disease and many patients have gastrointestinal side effects with semaglutide, one expert cautions.
The key findings were:
In STEP 5, combined with lifestyle intervention (a reduced-calorie meal plan and advice about physical activity), weekly injection of 2.4 mg semaglutide led to:
- 15.2% weight loss, compared with 2.6% weight loss with placebo at 2 years (P < .0001);
- 77% of patients losing at least 5% of their weight, compared with 34% of patients in the placebo group at 2 years (P < .0001);
- Significantly greater improvement in overall control of cravings, and craving for savory foods, in a subset of patients, versus placebo, but questionnaire scores for positive mood and craving for sweet foods were similar in both groups.
- In STEP 8, mean body weight at 68 weeks was 15.8% lower with 2.4 mg/week subcutaneous semaglutide plus lifestyle changes versus 6.4% lower with 3.0 mg/day subcutaneous liraglutide plus lifestyle changes (P < .001).
Can treat to a target weight-loss range
The undiminished weight loss efficacy in the 2-year data for STEP 5 “portends well,” said W. Timothy Garvey, MD, following his presentation of the results.
“I think this is a new era in obesity care,” said Dr. Garvey, director of the diabetes research center at the University of Alabama at Birmingham. Semaglutide “essentially doubles weight loss efficacy” compared to the other approved pharmacotherapies for obesity.
With this degree of potential weight loss, clinicians “can use weight as a biomarker and treat to a target [weight-loss] range,” he said.
Expounding on this in an interview, Dr. Garvey noted that, as stated in the 2016 American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) clinical practice guidelines for medical care of patients with obesity, of which he was lead author, “the objective of care in obesity is to increase health of patients and prevent or treat complications.”
Semaglutide “can treat to a range of weight loss of 10% to 20% in the majority of patients,” which is associated with improvements in cardiovascular and metabolic risk factors.
In STEP 5, of the 51% of patients in the semaglutide group who had prediabetes at enrollment, 80% had normal glycemia at 2 years; however, the trial was not powered nor designed to investigate this.
More data are needed to inform long-term care decisions. The ongoing SELECT cardiovascular outcomes trial of semaglutide, with expected primary study completion on Sept. 28, 2023, should provide more information.
Weight loss plus reduced cravings
In another presentation, Sean Wharton, MD, PharmD, said, “In adults with overweight or obesity, substantial weight loss with semaglutide 2.4 mg was accompanied by short- and long-term improvements in control of eating.”
“Most patients living with obesity who are attempting to decrease calories will have food cravings, based on the biological parameters of weight preservation,” Dr. Wharton, medical director at the Wharton Medical Clinic, in Hamilton, Ont., explained in an email.
The degree of craving varies from patient to patient, likely based on genetics, he added. Research in this field is still emerging.
“I believe that semaglutide 2.4 mg is a game-changer in the field of weight management, and it will change the dialogue for insurance plans and with policymakers regarding coverage for this medication,” said Dr. Wharton.
“The data from the STEP programs are very strong. I am certainly hoping for a change to bias against covering these medications that we have seen in the past,” he said.
Clinically meaningful weight loss
When presenting the STEP 8 findings, Domenica M. Rubino, MD, said: “Participants were significantly more likely to achieve clinically meaningful weight loss thresholds with semaglutide 2.4 mg versus liraglutide 3.0 mg, accompanied by greater improvements in cardiometabolic risk factors.”
For example, patients can have better mobility, which is important for quality of life, Dr. Rubino, director of the Washington Center for Weight Management and Research, Arlington, Virginia, noted.
A smaller percentage of patients respond to liraglutide, she added. Clinicians need to individualize treatment.
When asked, “How do you choose which medical therapy?” Dr. Rubino responded: “We sit and talk.” Finding the medical therapy that fits the patient depends on things such as the patient’s insurance coverage and ability to tolerate side effects such as dehydration, diarrhea, and nausea.
When asked, “How do you switch from liraglutide to semaglutide?” she noted that there are no current guidelines for this. “You have to be careful. Start on the lowest dose of Wegovy. Be cautious, conservative.”
Still early days, caveats remain
“The STEP trials as a group appear to be making the case that obesity may now be considered a medically manageable disease, based on the experience with semaglutide,” Julie R. Ingelfinger, MD, who was not involved with the research, commented in an email.
“STEP 5 and 8 may suggest that weight loss occurs and is sustainable in overweight persons without diabetes with one or more comorbidities or in obese persons without diabetes,” added Dr. Ingelfinger, professor of pediatrics, Harvard Medical School, consultant in pediatric nephrology, Massachusetts General Hospital, Boston, and deputy editor, The New England Journal of Medicine.
However, “even 2 years, in the case of STEP 5, and ~68 weeks in the case of STEP 8, may not be long enough to know whether semaglutide is as promising as these brief summaries (abstracts) suggest,” she cautioned.
“Obesity is a chronic condition, and very long-term therapy and management are required,” Dr. Ingelfinger continued.
“Further, it is hard to generalize when gastrointestinal adverse events are common in a study,” she said. For example, in STEP 8, they were just as common with semaglutide as with the comparator liraglutide, she noted.
“The racial and ethnic representativeness of these studies does not reflect population distributions in the U.S., limiting generalization,” she continued.
“So, there remain caveats in interpreting these data.”
STEP 5 weight loss efficacy and safety at 2 years
Garvey reported that STEP 5 was a phase 3b trial that randomized 304 adults in the United States, Canada, Hungary, Italy, and Spain, who were 18 years and older, with a body mass index (BMI) ≥27 kg/m2 with at least one weight-related comorbidity (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease) or a BMI ≥30 kg/m2, without type 2 diabetes, to receive semaglutide or placebo plus lifestyle intervention.
Most participants were women (78%) and White (93%). On average, they were 47 years old, weighed 106 kg (223.7 pounds), had a BMI of 38.5 kg/m2, a waist circumference of 115.7 cm (45.6 inches), and an A1c of 5.7%.
A total of 87% of patients in the semaglutide group and 73% of patients in the placebo group completed the trial.
At 104 weeks, participants were more likely to lose ≥10%, ≥15%, and ≥20% of body weight with semaglutide versus placebo (61.8% vs. 13.3%, 52.1% vs. 7.0%, and 36.1% vs. 2.3%, respectively; P < .0001 for all).
Patients in the semaglutide group had greater health improvements in cardiovascular risk factors (waist circumference, systolic and diastolic blood pressure, and C-reactive protein) and metabolic risk factors (A1c, fasting plasma glucose, fasting serum insulin, and triglycerides) than those in the placebo group (P < .05 for all).
Safety and tolerability were consistent with adverse events seen with this drug class, with no new safety signals.
Control of eating questionnaire findings at 2 years in STEP 5
Dr. Wharton and colleagues assessed changes in responses to the Control of Eating questionnaire at baseline and at 20, 52, and 104 weeks in patients from the U.S. and Canada in the STEP 5 trial (88 patients in the semaglutide group and 86 patients in the placebo group).
The questionnaire consisted of 19 questions grouped into four categories: control of food cravings, craving for savory foods (salty and spicy, dairy, or starchy foods), craving for sweet foods (chocolate, sweet foods, or fruit/fruit juice), and positive mood.
At week 104, patients in the semaglutide group had significantly greater improvements in scores for craving for salty and spicy, dairy, and starchy foods, and resisting cravings.
Semaglutide versus liraglutide, 68-week efficacy and safety in STEP 8
STEP 8 randomized 338 U.S. adults without diabetes and a BMI of ≥27 kg/m2 plus one or more weight-related comorbidities or a BMI of ≥30 kg/m2 3:1 to semaglutide 2.4 mg once weekly (n = 126) or matching placebo, or 3:1 liraglutide 3.0 mg once daily (n = 127) or matching placebo, plus lifestyle intervention.
Most participants were women (78%) and were a mean age of 49, had a mean body weight of 104.5 kg, and had a mean BMI of 37.5 kg/m2.
In STEP 8, more participants achieved ≥10%, ≥15%, and ≥20% weight loss with semaglutide than with liraglutide (70.9% vs. 25.6%, 55.6% vs. 12.0%, and 38.5% vs. 6.0%, respectively; P < .001 for all odds ratios).
Semaglutide improved waist circumference, A1c, and C-reactive protein versus liraglutide (unadjusted P < .001 for all).
Gastrointestinal adverse events were reported by 84% and 83% of participants receiving semaglutide and liraglutide, respectively. Most events were mild/moderate and transient, with prevalence declining over time.
Fewer participants stopped treatment due to adverse events with semaglutide than liraglutide (3.2% vs. 12.6%).
Dr. Garvey has reported serving as a site principal investigator for multicentered clinical trials sponsored by his university and funded by Eli Lilly, Novo Nordisk, and Pfizer. Dr. Wharton has reported financial ties to Novo Nordisk, Bausch Health Canada, Eli Lily, and Boehringer Ingelheim Canada. Dr. Rubino has reported ties to Boehringer Ingelheim and AstraZeneca. Dr. Ingelfinger has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The STEP 5 clinical trial extends favorable weight loss from 1 year out to 2 years for the glucagon-like peptide-1 (GLP-1) agonist semaglutide (Wegovy, Novo Nordisk), given as a once-weekly 2.4-mg subcutaneous injection, and some food cravings were improved in a subgroup analysis.
In another study, STEP 8, weight loss was greater at 68 weeks with semaglutide subcutaneous injection than with a 3-mg daily subcutaneous injection of another GLP-1 agonist, liraglutide (Saxenda, Novo Nordisk), approved earlier for weight loss.
Researchers presented these promising outcomes, with no new safety signals, at ObesityWeek® 2021.
However, there is more to learn about the drug class, researchers agree. Follow-up is still relatively short for a chronic disease and many patients have gastrointestinal side effects with semaglutide, one expert cautions.
The key findings were:
In STEP 5, combined with lifestyle intervention (a reduced-calorie meal plan and advice about physical activity), weekly injection of 2.4 mg semaglutide led to:
- 15.2% weight loss, compared with 2.6% weight loss with placebo at 2 years (P < .0001);
- 77% of patients losing at least 5% of their weight, compared with 34% of patients in the placebo group at 2 years (P < .0001);
- Significantly greater improvement in overall control of cravings, and craving for savory foods, in a subset of patients, versus placebo, but questionnaire scores for positive mood and craving for sweet foods were similar in both groups.
- In STEP 8, mean body weight at 68 weeks was 15.8% lower with 2.4 mg/week subcutaneous semaglutide plus lifestyle changes versus 6.4% lower with 3.0 mg/day subcutaneous liraglutide plus lifestyle changes (P < .001).
Can treat to a target weight-loss range
The undiminished weight loss efficacy in the 2-year data for STEP 5 “portends well,” said W. Timothy Garvey, MD, following his presentation of the results.
“I think this is a new era in obesity care,” said Dr. Garvey, director of the diabetes research center at the University of Alabama at Birmingham. Semaglutide “essentially doubles weight loss efficacy” compared to the other approved pharmacotherapies for obesity.
With this degree of potential weight loss, clinicians “can use weight as a biomarker and treat to a target [weight-loss] range,” he said.
Expounding on this in an interview, Dr. Garvey noted that, as stated in the 2016 American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) clinical practice guidelines for medical care of patients with obesity, of which he was lead author, “the objective of care in obesity is to increase health of patients and prevent or treat complications.”
Semaglutide “can treat to a range of weight loss of 10% to 20% in the majority of patients,” which is associated with improvements in cardiovascular and metabolic risk factors.
In STEP 5, of the 51% of patients in the semaglutide group who had prediabetes at enrollment, 80% had normal glycemia at 2 years; however, the trial was not powered nor designed to investigate this.
More data are needed to inform long-term care decisions. The ongoing SELECT cardiovascular outcomes trial of semaglutide, with expected primary study completion on Sept. 28, 2023, should provide more information.
Weight loss plus reduced cravings
In another presentation, Sean Wharton, MD, PharmD, said, “In adults with overweight or obesity, substantial weight loss with semaglutide 2.4 mg was accompanied by short- and long-term improvements in control of eating.”
“Most patients living with obesity who are attempting to decrease calories will have food cravings, based on the biological parameters of weight preservation,” Dr. Wharton, medical director at the Wharton Medical Clinic, in Hamilton, Ont., explained in an email.
The degree of craving varies from patient to patient, likely based on genetics, he added. Research in this field is still emerging.
“I believe that semaglutide 2.4 mg is a game-changer in the field of weight management, and it will change the dialogue for insurance plans and with policymakers regarding coverage for this medication,” said Dr. Wharton.
“The data from the STEP programs are very strong. I am certainly hoping for a change to bias against covering these medications that we have seen in the past,” he said.
Clinically meaningful weight loss
When presenting the STEP 8 findings, Domenica M. Rubino, MD, said: “Participants were significantly more likely to achieve clinically meaningful weight loss thresholds with semaglutide 2.4 mg versus liraglutide 3.0 mg, accompanied by greater improvements in cardiometabolic risk factors.”
For example, patients can have better mobility, which is important for quality of life, Dr. Rubino, director of the Washington Center for Weight Management and Research, Arlington, Virginia, noted.
A smaller percentage of patients respond to liraglutide, she added. Clinicians need to individualize treatment.
When asked, “How do you choose which medical therapy?” Dr. Rubino responded: “We sit and talk.” Finding the medical therapy that fits the patient depends on things such as the patient’s insurance coverage and ability to tolerate side effects such as dehydration, diarrhea, and nausea.
When asked, “How do you switch from liraglutide to semaglutide?” she noted that there are no current guidelines for this. “You have to be careful. Start on the lowest dose of Wegovy. Be cautious, conservative.”
Still early days, caveats remain
“The STEP trials as a group appear to be making the case that obesity may now be considered a medically manageable disease, based on the experience with semaglutide,” Julie R. Ingelfinger, MD, who was not involved with the research, commented in an email.
“STEP 5 and 8 may suggest that weight loss occurs and is sustainable in overweight persons without diabetes with one or more comorbidities or in obese persons without diabetes,” added Dr. Ingelfinger, professor of pediatrics, Harvard Medical School, consultant in pediatric nephrology, Massachusetts General Hospital, Boston, and deputy editor, The New England Journal of Medicine.
However, “even 2 years, in the case of STEP 5, and ~68 weeks in the case of STEP 8, may not be long enough to know whether semaglutide is as promising as these brief summaries (abstracts) suggest,” she cautioned.
“Obesity is a chronic condition, and very long-term therapy and management are required,” Dr. Ingelfinger continued.
“Further, it is hard to generalize when gastrointestinal adverse events are common in a study,” she said. For example, in STEP 8, they were just as common with semaglutide as with the comparator liraglutide, she noted.
“The racial and ethnic representativeness of these studies does not reflect population distributions in the U.S., limiting generalization,” she continued.
“So, there remain caveats in interpreting these data.”
STEP 5 weight loss efficacy and safety at 2 years
Garvey reported that STEP 5 was a phase 3b trial that randomized 304 adults in the United States, Canada, Hungary, Italy, and Spain, who were 18 years and older, with a body mass index (BMI) ≥27 kg/m2 with at least one weight-related comorbidity (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease) or a BMI ≥30 kg/m2, without type 2 diabetes, to receive semaglutide or placebo plus lifestyle intervention.
Most participants were women (78%) and White (93%). On average, they were 47 years old, weighed 106 kg (223.7 pounds), had a BMI of 38.5 kg/m2, a waist circumference of 115.7 cm (45.6 inches), and an A1c of 5.7%.
A total of 87% of patients in the semaglutide group and 73% of patients in the placebo group completed the trial.
At 104 weeks, participants were more likely to lose ≥10%, ≥15%, and ≥20% of body weight with semaglutide versus placebo (61.8% vs. 13.3%, 52.1% vs. 7.0%, and 36.1% vs. 2.3%, respectively; P < .0001 for all).
Patients in the semaglutide group had greater health improvements in cardiovascular risk factors (waist circumference, systolic and diastolic blood pressure, and C-reactive protein) and metabolic risk factors (A1c, fasting plasma glucose, fasting serum insulin, and triglycerides) than those in the placebo group (P < .05 for all).
Safety and tolerability were consistent with adverse events seen with this drug class, with no new safety signals.
Control of eating questionnaire findings at 2 years in STEP 5
Dr. Wharton and colleagues assessed changes in responses to the Control of Eating questionnaire at baseline and at 20, 52, and 104 weeks in patients from the U.S. and Canada in the STEP 5 trial (88 patients in the semaglutide group and 86 patients in the placebo group).
The questionnaire consisted of 19 questions grouped into four categories: control of food cravings, craving for savory foods (salty and spicy, dairy, or starchy foods), craving for sweet foods (chocolate, sweet foods, or fruit/fruit juice), and positive mood.
At week 104, patients in the semaglutide group had significantly greater improvements in scores for craving for salty and spicy, dairy, and starchy foods, and resisting cravings.
Semaglutide versus liraglutide, 68-week efficacy and safety in STEP 8
STEP 8 randomized 338 U.S. adults without diabetes and a BMI of ≥27 kg/m2 plus one or more weight-related comorbidities or a BMI of ≥30 kg/m2 3:1 to semaglutide 2.4 mg once weekly (n = 126) or matching placebo, or 3:1 liraglutide 3.0 mg once daily (n = 127) or matching placebo, plus lifestyle intervention.
Most participants were women (78%) and were a mean age of 49, had a mean body weight of 104.5 kg, and had a mean BMI of 37.5 kg/m2.
In STEP 8, more participants achieved ≥10%, ≥15%, and ≥20% weight loss with semaglutide than with liraglutide (70.9% vs. 25.6%, 55.6% vs. 12.0%, and 38.5% vs. 6.0%, respectively; P < .001 for all odds ratios).
Semaglutide improved waist circumference, A1c, and C-reactive protein versus liraglutide (unadjusted P < .001 for all).
Gastrointestinal adverse events were reported by 84% and 83% of participants receiving semaglutide and liraglutide, respectively. Most events were mild/moderate and transient, with prevalence declining over time.
Fewer participants stopped treatment due to adverse events with semaglutide than liraglutide (3.2% vs. 12.6%).
Dr. Garvey has reported serving as a site principal investigator for multicentered clinical trials sponsored by his university and funded by Eli Lilly, Novo Nordisk, and Pfizer. Dr. Wharton has reported financial ties to Novo Nordisk, Bausch Health Canada, Eli Lily, and Boehringer Ingelheim Canada. Dr. Rubino has reported ties to Boehringer Ingelheim and AstraZeneca. Dr. Ingelfinger has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The STEP 5 clinical trial extends favorable weight loss from 1 year out to 2 years for the glucagon-like peptide-1 (GLP-1) agonist semaglutide (Wegovy, Novo Nordisk), given as a once-weekly 2.4-mg subcutaneous injection, and some food cravings were improved in a subgroup analysis.
In another study, STEP 8, weight loss was greater at 68 weeks with semaglutide subcutaneous injection than with a 3-mg daily subcutaneous injection of another GLP-1 agonist, liraglutide (Saxenda, Novo Nordisk), approved earlier for weight loss.
Researchers presented these promising outcomes, with no new safety signals, at ObesityWeek® 2021.
However, there is more to learn about the drug class, researchers agree. Follow-up is still relatively short for a chronic disease and many patients have gastrointestinal side effects with semaglutide, one expert cautions.
The key findings were:
In STEP 5, combined with lifestyle intervention (a reduced-calorie meal plan and advice about physical activity), weekly injection of 2.4 mg semaglutide led to:
- 15.2% weight loss, compared with 2.6% weight loss with placebo at 2 years (P < .0001);
- 77% of patients losing at least 5% of their weight, compared with 34% of patients in the placebo group at 2 years (P < .0001);
- Significantly greater improvement in overall control of cravings, and craving for savory foods, in a subset of patients, versus placebo, but questionnaire scores for positive mood and craving for sweet foods were similar in both groups.
- In STEP 8, mean body weight at 68 weeks was 15.8% lower with 2.4 mg/week subcutaneous semaglutide plus lifestyle changes versus 6.4% lower with 3.0 mg/day subcutaneous liraglutide plus lifestyle changes (P < .001).
Can treat to a target weight-loss range
The undiminished weight loss efficacy in the 2-year data for STEP 5 “portends well,” said W. Timothy Garvey, MD, following his presentation of the results.
“I think this is a new era in obesity care,” said Dr. Garvey, director of the diabetes research center at the University of Alabama at Birmingham. Semaglutide “essentially doubles weight loss efficacy” compared to the other approved pharmacotherapies for obesity.
With this degree of potential weight loss, clinicians “can use weight as a biomarker and treat to a target [weight-loss] range,” he said.
Expounding on this in an interview, Dr. Garvey noted that, as stated in the 2016 American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) clinical practice guidelines for medical care of patients with obesity, of which he was lead author, “the objective of care in obesity is to increase health of patients and prevent or treat complications.”
Semaglutide “can treat to a range of weight loss of 10% to 20% in the majority of patients,” which is associated with improvements in cardiovascular and metabolic risk factors.
In STEP 5, of the 51% of patients in the semaglutide group who had prediabetes at enrollment, 80% had normal glycemia at 2 years; however, the trial was not powered nor designed to investigate this.
More data are needed to inform long-term care decisions. The ongoing SELECT cardiovascular outcomes trial of semaglutide, with expected primary study completion on Sept. 28, 2023, should provide more information.
Weight loss plus reduced cravings
In another presentation, Sean Wharton, MD, PharmD, said, “In adults with overweight or obesity, substantial weight loss with semaglutide 2.4 mg was accompanied by short- and long-term improvements in control of eating.”
“Most patients living with obesity who are attempting to decrease calories will have food cravings, based on the biological parameters of weight preservation,” Dr. Wharton, medical director at the Wharton Medical Clinic, in Hamilton, Ont., explained in an email.
The degree of craving varies from patient to patient, likely based on genetics, he added. Research in this field is still emerging.
“I believe that semaglutide 2.4 mg is a game-changer in the field of weight management, and it will change the dialogue for insurance plans and with policymakers regarding coverage for this medication,” said Dr. Wharton.
“The data from the STEP programs are very strong. I am certainly hoping for a change to bias against covering these medications that we have seen in the past,” he said.
Clinically meaningful weight loss
When presenting the STEP 8 findings, Domenica M. Rubino, MD, said: “Participants were significantly more likely to achieve clinically meaningful weight loss thresholds with semaglutide 2.4 mg versus liraglutide 3.0 mg, accompanied by greater improvements in cardiometabolic risk factors.”
For example, patients can have better mobility, which is important for quality of life, Dr. Rubino, director of the Washington Center for Weight Management and Research, Arlington, Virginia, noted.
A smaller percentage of patients respond to liraglutide, she added. Clinicians need to individualize treatment.
When asked, “How do you choose which medical therapy?” Dr. Rubino responded: “We sit and talk.” Finding the medical therapy that fits the patient depends on things such as the patient’s insurance coverage and ability to tolerate side effects such as dehydration, diarrhea, and nausea.
When asked, “How do you switch from liraglutide to semaglutide?” she noted that there are no current guidelines for this. “You have to be careful. Start on the lowest dose of Wegovy. Be cautious, conservative.”
Still early days, caveats remain
“The STEP trials as a group appear to be making the case that obesity may now be considered a medically manageable disease, based on the experience with semaglutide,” Julie R. Ingelfinger, MD, who was not involved with the research, commented in an email.
“STEP 5 and 8 may suggest that weight loss occurs and is sustainable in overweight persons without diabetes with one or more comorbidities or in obese persons without diabetes,” added Dr. Ingelfinger, professor of pediatrics, Harvard Medical School, consultant in pediatric nephrology, Massachusetts General Hospital, Boston, and deputy editor, The New England Journal of Medicine.
However, “even 2 years, in the case of STEP 5, and ~68 weeks in the case of STEP 8, may not be long enough to know whether semaglutide is as promising as these brief summaries (abstracts) suggest,” she cautioned.
“Obesity is a chronic condition, and very long-term therapy and management are required,” Dr. Ingelfinger continued.
“Further, it is hard to generalize when gastrointestinal adverse events are common in a study,” she said. For example, in STEP 8, they were just as common with semaglutide as with the comparator liraglutide, she noted.
“The racial and ethnic representativeness of these studies does not reflect population distributions in the U.S., limiting generalization,” she continued.
“So, there remain caveats in interpreting these data.”
STEP 5 weight loss efficacy and safety at 2 years
Garvey reported that STEP 5 was a phase 3b trial that randomized 304 adults in the United States, Canada, Hungary, Italy, and Spain, who were 18 years and older, with a body mass index (BMI) ≥27 kg/m2 with at least one weight-related comorbidity (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease) or a BMI ≥30 kg/m2, without type 2 diabetes, to receive semaglutide or placebo plus lifestyle intervention.
Most participants were women (78%) and White (93%). On average, they were 47 years old, weighed 106 kg (223.7 pounds), had a BMI of 38.5 kg/m2, a waist circumference of 115.7 cm (45.6 inches), and an A1c of 5.7%.
A total of 87% of patients in the semaglutide group and 73% of patients in the placebo group completed the trial.
At 104 weeks, participants were more likely to lose ≥10%, ≥15%, and ≥20% of body weight with semaglutide versus placebo (61.8% vs. 13.3%, 52.1% vs. 7.0%, and 36.1% vs. 2.3%, respectively; P < .0001 for all).
Patients in the semaglutide group had greater health improvements in cardiovascular risk factors (waist circumference, systolic and diastolic blood pressure, and C-reactive protein) and metabolic risk factors (A1c, fasting plasma glucose, fasting serum insulin, and triglycerides) than those in the placebo group (P < .05 for all).
Safety and tolerability were consistent with adverse events seen with this drug class, with no new safety signals.
Control of eating questionnaire findings at 2 years in STEP 5
Dr. Wharton and colleagues assessed changes in responses to the Control of Eating questionnaire at baseline and at 20, 52, and 104 weeks in patients from the U.S. and Canada in the STEP 5 trial (88 patients in the semaglutide group and 86 patients in the placebo group).
The questionnaire consisted of 19 questions grouped into four categories: control of food cravings, craving for savory foods (salty and spicy, dairy, or starchy foods), craving for sweet foods (chocolate, sweet foods, or fruit/fruit juice), and positive mood.
At week 104, patients in the semaglutide group had significantly greater improvements in scores for craving for salty and spicy, dairy, and starchy foods, and resisting cravings.
Semaglutide versus liraglutide, 68-week efficacy and safety in STEP 8
STEP 8 randomized 338 U.S. adults without diabetes and a BMI of ≥27 kg/m2 plus one or more weight-related comorbidities or a BMI of ≥30 kg/m2 3:1 to semaglutide 2.4 mg once weekly (n = 126) or matching placebo, or 3:1 liraglutide 3.0 mg once daily (n = 127) or matching placebo, plus lifestyle intervention.
Most participants were women (78%) and were a mean age of 49, had a mean body weight of 104.5 kg, and had a mean BMI of 37.5 kg/m2.
In STEP 8, more participants achieved ≥10%, ≥15%, and ≥20% weight loss with semaglutide than with liraglutide (70.9% vs. 25.6%, 55.6% vs. 12.0%, and 38.5% vs. 6.0%, respectively; P < .001 for all odds ratios).
Semaglutide improved waist circumference, A1c, and C-reactive protein versus liraglutide (unadjusted P < .001 for all).
Gastrointestinal adverse events were reported by 84% and 83% of participants receiving semaglutide and liraglutide, respectively. Most events were mild/moderate and transient, with prevalence declining over time.
Fewer participants stopped treatment due to adverse events with semaglutide than liraglutide (3.2% vs. 12.6%).
Dr. Garvey has reported serving as a site principal investigator for multicentered clinical trials sponsored by his university and funded by Eli Lilly, Novo Nordisk, and Pfizer. Dr. Wharton has reported financial ties to Novo Nordisk, Bausch Health Canada, Eli Lily, and Boehringer Ingelheim Canada. Dr. Rubino has reported ties to Boehringer Ingelheim and AstraZeneca. Dr. Ingelfinger has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Single infusion of ketamine rapidly reduces suicidal thoughts
A single infusion of ketamine rapidly improves distorted thinking and reasoning to reduce suicidal thoughts, independent of the drug’s effect on severe depression, new research shows.
“Previously it was shown that ketamine rapidly improved depression and that explained part of the rapid improvement in suicidal ideation,” senior author J. John Mann, MD, with Columbia University, New York, said in an interview.
“What was unclear was what else changed that could decrease suicidal ideation and the risk for suicidal behavior. This study identifies a second new domain of improvement – namely rapid improvement in several cognitive functions that can potentially reduce suicide risk,” said Dr. Mann.
The study was published online Nov. 2, 2021, in the Journal of Clinical Psychiatry.
Boosts cognitive function
A total of 78 adults with major depressive disorder and clinically significant suicidal ideation underwent neuropsychological testing before, and 1 day after, double-blind treatment with a single intravenous infusion of ketamine or midazolam.
“Ketamine produced rapid improvement in suicidal ideation and mood” compared with midazolam, the authors reported.
Ketamine was linked to specific improvement in reaction time and cognitive control/interference processing – a measure that has been associated with previous suicide attempt in depression.
A subgroup of patients whose suicidal ideation did not remit on midazolam were later treated with unblinded ketamine and retested. In these individuals, reaction time and cognitive control/interference processing also improved relative to preketamine assessments.
Neurocognitive improvement, however, was not correlated with changes in depression, suicidal thinking, or general mood, the researchers noted.
Nonetheless, they say ketamine had a “positive therapeutic effect” on neurocognition 1 day after treatment on at least one measure associated with suicidal behavior in the context of depression.
The results suggest “additional independent therapeutic effects for ketamine in the treatment of depressed patients at risk for suicidal behavior,” they wrote.
“Ketamine modulates many neurotransmitter systems including glutamate transmission which is crucial for learning and memory. It increases the number of synapses or connections between neurons. These effects are fundamental to cognition and are logical explanations of the beneficial effects observed in this study,” Dr. Mann said in an interview.
“Our study helped us gain a better understanding of how ketamine works in the brain and how quickly it can improve distorted thinking. study investigator Ravi. N. Shah, MD, chief innovation officer, Columbia Psychiatry, said in a news release.
Important research with caveats
In a comment, James Murrough, MD, PhD, director of the Depression and Anxiety Center for Discovery and Treatment at Mount Sinai in New York, said the study is important and “adds to a growing understanding of how ketamine affects brain systems and thinking in the context of depression and suicide risk.”
“One reason this study is significant is that prior studies have shown that ketamine can have harmful effects on cognitive functioning in the context of ketamine misuse and exposures to high doses for long periods of time,” Dr. Murrough, who wasn’t involved in the study, said in an interview.
“In contrast in this study, a single low-dose treatment of ketamine can have the opposite effects, actually boosting some markers of cognitive functioning, at least in the short-term,” he noted.
Dr. Murrough said one caveat to the study is that it only examined the effect of ketamine on cognition once, 1 day after a single treatment.
“While this is an important initial observation, we don’t yet have any understanding of how persistent this effect on cognition is, or how this observed change may be related to any benefit ketamine may have on depression or suicide risk,” Dr. Murrough said.
“In fact, the researchers found that there was no association between change in cognitive functioning following ketamine and change in depression or suicidal thinking. The patients who showed improved cognitive function following ketamine did not differ in terms of mood or suicide risk compared to patients who did not show an improvement in cognition,” Dr. Murrough noted.
“This raises the important question of what is the relevance of change in cognition to the potential benefits of ketamine. This is an important area and should be the focus of future research in order to improve outcomes for patients with depression and who are at risk for suicide,” he added.
Also weighing in, Roger S. McIntyre, MD, professor of psychiatry and pharmacology and head of the mood disorders psychopharmacology unit, University of Toronto, said the study is “very interesting and in keeping” with some previous work that he and his colleagues have done showing that ketamine “seems to benefit aspects of cognition which is a core element in depression.”
“It’s a testable hypothesis that the improvement in cognition now being reported and replicated could play some role in the improved quality of life and functioning with this treatment and as well reduce reducing suicide,” said Dr. McIntyre.
This study was supported by the National Institute of Mental Health. Dr. Mann receives royalties for commercial use of the Columbia-Suicide Severity Rating Scale, which was not used in this study. Dr. Murrough’s institution was involved in research involving esketamine (Spravato) for treatment-resistant depression and receives financial remuneration from the manufacturer of esketamine. Dr. McIntyre has received research grant support from the Canadian Institutes of Health Research/Global Alliance for Chronic Diseases/Chinese National Natural Research Foundation and speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, Eisai, Minerva, Intra-Cellular, and AbbVie. Dr. McIntyre is also CEO of AltMed.
A version of this article first appeared on Medscape.com.
A single infusion of ketamine rapidly improves distorted thinking and reasoning to reduce suicidal thoughts, independent of the drug’s effect on severe depression, new research shows.
“Previously it was shown that ketamine rapidly improved depression and that explained part of the rapid improvement in suicidal ideation,” senior author J. John Mann, MD, with Columbia University, New York, said in an interview.
“What was unclear was what else changed that could decrease suicidal ideation and the risk for suicidal behavior. This study identifies a second new domain of improvement – namely rapid improvement in several cognitive functions that can potentially reduce suicide risk,” said Dr. Mann.
The study was published online Nov. 2, 2021, in the Journal of Clinical Psychiatry.
Boosts cognitive function
A total of 78 adults with major depressive disorder and clinically significant suicidal ideation underwent neuropsychological testing before, and 1 day after, double-blind treatment with a single intravenous infusion of ketamine or midazolam.
“Ketamine produced rapid improvement in suicidal ideation and mood” compared with midazolam, the authors reported.
Ketamine was linked to specific improvement in reaction time and cognitive control/interference processing – a measure that has been associated with previous suicide attempt in depression.
A subgroup of patients whose suicidal ideation did not remit on midazolam were later treated with unblinded ketamine and retested. In these individuals, reaction time and cognitive control/interference processing also improved relative to preketamine assessments.
Neurocognitive improvement, however, was not correlated with changes in depression, suicidal thinking, or general mood, the researchers noted.
Nonetheless, they say ketamine had a “positive therapeutic effect” on neurocognition 1 day after treatment on at least one measure associated with suicidal behavior in the context of depression.
The results suggest “additional independent therapeutic effects for ketamine in the treatment of depressed patients at risk for suicidal behavior,” they wrote.
“Ketamine modulates many neurotransmitter systems including glutamate transmission which is crucial for learning and memory. It increases the number of synapses or connections between neurons. These effects are fundamental to cognition and are logical explanations of the beneficial effects observed in this study,” Dr. Mann said in an interview.
“Our study helped us gain a better understanding of how ketamine works in the brain and how quickly it can improve distorted thinking. study investigator Ravi. N. Shah, MD, chief innovation officer, Columbia Psychiatry, said in a news release.
Important research with caveats
In a comment, James Murrough, MD, PhD, director of the Depression and Anxiety Center for Discovery and Treatment at Mount Sinai in New York, said the study is important and “adds to a growing understanding of how ketamine affects brain systems and thinking in the context of depression and suicide risk.”
“One reason this study is significant is that prior studies have shown that ketamine can have harmful effects on cognitive functioning in the context of ketamine misuse and exposures to high doses for long periods of time,” Dr. Murrough, who wasn’t involved in the study, said in an interview.
“In contrast in this study, a single low-dose treatment of ketamine can have the opposite effects, actually boosting some markers of cognitive functioning, at least in the short-term,” he noted.
Dr. Murrough said one caveat to the study is that it only examined the effect of ketamine on cognition once, 1 day after a single treatment.
“While this is an important initial observation, we don’t yet have any understanding of how persistent this effect on cognition is, or how this observed change may be related to any benefit ketamine may have on depression or suicide risk,” Dr. Murrough said.
“In fact, the researchers found that there was no association between change in cognitive functioning following ketamine and change in depression or suicidal thinking. The patients who showed improved cognitive function following ketamine did not differ in terms of mood or suicide risk compared to patients who did not show an improvement in cognition,” Dr. Murrough noted.
“This raises the important question of what is the relevance of change in cognition to the potential benefits of ketamine. This is an important area and should be the focus of future research in order to improve outcomes for patients with depression and who are at risk for suicide,” he added.
Also weighing in, Roger S. McIntyre, MD, professor of psychiatry and pharmacology and head of the mood disorders psychopharmacology unit, University of Toronto, said the study is “very interesting and in keeping” with some previous work that he and his colleagues have done showing that ketamine “seems to benefit aspects of cognition which is a core element in depression.”
“It’s a testable hypothesis that the improvement in cognition now being reported and replicated could play some role in the improved quality of life and functioning with this treatment and as well reduce reducing suicide,” said Dr. McIntyre.
This study was supported by the National Institute of Mental Health. Dr. Mann receives royalties for commercial use of the Columbia-Suicide Severity Rating Scale, which was not used in this study. Dr. Murrough’s institution was involved in research involving esketamine (Spravato) for treatment-resistant depression and receives financial remuneration from the manufacturer of esketamine. Dr. McIntyre has received research grant support from the Canadian Institutes of Health Research/Global Alliance for Chronic Diseases/Chinese National Natural Research Foundation and speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, Eisai, Minerva, Intra-Cellular, and AbbVie. Dr. McIntyre is also CEO of AltMed.
A version of this article first appeared on Medscape.com.
A single infusion of ketamine rapidly improves distorted thinking and reasoning to reduce suicidal thoughts, independent of the drug’s effect on severe depression, new research shows.
“Previously it was shown that ketamine rapidly improved depression and that explained part of the rapid improvement in suicidal ideation,” senior author J. John Mann, MD, with Columbia University, New York, said in an interview.
“What was unclear was what else changed that could decrease suicidal ideation and the risk for suicidal behavior. This study identifies a second new domain of improvement – namely rapid improvement in several cognitive functions that can potentially reduce suicide risk,” said Dr. Mann.
The study was published online Nov. 2, 2021, in the Journal of Clinical Psychiatry.
Boosts cognitive function
A total of 78 adults with major depressive disorder and clinically significant suicidal ideation underwent neuropsychological testing before, and 1 day after, double-blind treatment with a single intravenous infusion of ketamine or midazolam.
“Ketamine produced rapid improvement in suicidal ideation and mood” compared with midazolam, the authors reported.
Ketamine was linked to specific improvement in reaction time and cognitive control/interference processing – a measure that has been associated with previous suicide attempt in depression.
A subgroup of patients whose suicidal ideation did not remit on midazolam were later treated with unblinded ketamine and retested. In these individuals, reaction time and cognitive control/interference processing also improved relative to preketamine assessments.
Neurocognitive improvement, however, was not correlated with changes in depression, suicidal thinking, or general mood, the researchers noted.
Nonetheless, they say ketamine had a “positive therapeutic effect” on neurocognition 1 day after treatment on at least one measure associated with suicidal behavior in the context of depression.
The results suggest “additional independent therapeutic effects for ketamine in the treatment of depressed patients at risk for suicidal behavior,” they wrote.
“Ketamine modulates many neurotransmitter systems including glutamate transmission which is crucial for learning and memory. It increases the number of synapses or connections between neurons. These effects are fundamental to cognition and are logical explanations of the beneficial effects observed in this study,” Dr. Mann said in an interview.
“Our study helped us gain a better understanding of how ketamine works in the brain and how quickly it can improve distorted thinking. study investigator Ravi. N. Shah, MD, chief innovation officer, Columbia Psychiatry, said in a news release.
Important research with caveats
In a comment, James Murrough, MD, PhD, director of the Depression and Anxiety Center for Discovery and Treatment at Mount Sinai in New York, said the study is important and “adds to a growing understanding of how ketamine affects brain systems and thinking in the context of depression and suicide risk.”
“One reason this study is significant is that prior studies have shown that ketamine can have harmful effects on cognitive functioning in the context of ketamine misuse and exposures to high doses for long periods of time,” Dr. Murrough, who wasn’t involved in the study, said in an interview.
“In contrast in this study, a single low-dose treatment of ketamine can have the opposite effects, actually boosting some markers of cognitive functioning, at least in the short-term,” he noted.
Dr. Murrough said one caveat to the study is that it only examined the effect of ketamine on cognition once, 1 day after a single treatment.
“While this is an important initial observation, we don’t yet have any understanding of how persistent this effect on cognition is, or how this observed change may be related to any benefit ketamine may have on depression or suicide risk,” Dr. Murrough said.
“In fact, the researchers found that there was no association between change in cognitive functioning following ketamine and change in depression or suicidal thinking. The patients who showed improved cognitive function following ketamine did not differ in terms of mood or suicide risk compared to patients who did not show an improvement in cognition,” Dr. Murrough noted.
“This raises the important question of what is the relevance of change in cognition to the potential benefits of ketamine. This is an important area and should be the focus of future research in order to improve outcomes for patients with depression and who are at risk for suicide,” he added.
Also weighing in, Roger S. McIntyre, MD, professor of psychiatry and pharmacology and head of the mood disorders psychopharmacology unit, University of Toronto, said the study is “very interesting and in keeping” with some previous work that he and his colleagues have done showing that ketamine “seems to benefit aspects of cognition which is a core element in depression.”
“It’s a testable hypothesis that the improvement in cognition now being reported and replicated could play some role in the improved quality of life and functioning with this treatment and as well reduce reducing suicide,” said Dr. McIntyre.
This study was supported by the National Institute of Mental Health. Dr. Mann receives royalties for commercial use of the Columbia-Suicide Severity Rating Scale, which was not used in this study. Dr. Murrough’s institution was involved in research involving esketamine (Spravato) for treatment-resistant depression and receives financial remuneration from the manufacturer of esketamine. Dr. McIntyre has received research grant support from the Canadian Institutes of Health Research/Global Alliance for Chronic Diseases/Chinese National Natural Research Foundation and speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, Eisai, Minerva, Intra-Cellular, and AbbVie. Dr. McIntyre is also CEO of AltMed.
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF CLINICAL PSYCHIATRY
Treating young adults with high LDL may be cost-effective
Treating elevated low-density lipoprotein cholesterol (LDL-C) in adults younger than 40 with statins is highly cost-effective in men, and intermediately cost-effective in women, a new report suggests.
In a simulated model based on data from the U.S. National Health and Nutrition Examination Survey (NHANES), lipid lowering with statins or lifestyle interventions in this age group would prevent or reduce the risk of atherosclerotic cardiovascular disease (ASCVD) and improve quality of life in later years.
The findings were published online Nov. 8 in the Journal of the American College of Cardiology.
“My group does epidemiologic analyses with cohort studies as well as health economic analyses like this one, and if you have long-term longitudinal observation, you see that the early exposures are important for what happens later,” senior author Andrew E. Moran, MD, Columbia University Irving Medical Center, New York, told this news organization.
“But when it comes to treatment studies that a lot of the treatment guidelines are based on, those are usually short-term, and they usually enroll older people. We saw the gap in the evidence that this paper tries to fill,” Dr. Moran said.
His group used a computer simulation model to synthesize evidence from observational cohort studies and clinical trials of statin treatment, as well as health services data on the costs of medicines and treatments.
Combining information from these sources, the investigators made their best estimates of the potential health benefits and costs of treating high cholesterol earlier in life, compared with standard care, which was statin treatment at age 40, or if LDL-C was 190 mg/dL or greater.
Lipid lowering incremental to standard care with moderate-intensity statins or intensive lifestyle interventions was simulated starting when young adult LDL-C was either ≥160 mg/dL or ≥130 mg/dL.
They found that approximately 27% of young adults who are free of ASCVD have LDL-C ≥130 mg/dL, and 9% have LDL-C of ≥160 mg/dL.
Their model projected that treating adults younger than 40 with statins or lifestyle interventions would prevent lifetime ASCVD events and increase quality-adjusted life years (QALYs) compared with standard care, which would begin treatment at age 40.
Incremental cost-effectiveness ratios (ICERs) were $31,000/QALY for statin treatment in young adult men with LDL-C ≥130 mg/dL, and $106,000/QALY for statin treatment in young women with LDL-C ≥130 mg/dL.
Intensive lifestyle intervention was more costly and less effective than statin therapy.
“We are straining to find these young adults with very high cholesterol,” Dr. Moran noted. “A lot of young adults don’t even see a doctor. This is an argument for engaging them in their health care and getting them involved in some basic screening. Atherosclerosis is a long-term process that starts in childhood for a lot of people.”
More innovative approaches may be needed, because the traditional health care system is not doing a good job of reaching young adults, he added. “Many of them may not have adequate health insurance. They need health care in nontraditional ways; convenience is really important for them. Perhaps part of the solution here is to think about ways of reaching this particular group that is not engaged with health care generally.”
Time to relax the age 40 threshold
The U.S. Preventive Services Task Force and the American College of Cardiology/American Heart Association should emphasize lifetime risk of elevated cholesterol, Paul A. Heidenreich, MD, MS, Stanford University School of Medicine, California, and colleagues write in an accompanying editorial.
“In addition to calculating 10-year risk, we should calculate years of life lost (or QALYs lost) from unhealthy LDL-C levels, and both lifestyle and pharmacologic treatment should be considered to treat high LDL-C in adults regardless of age. We also need to communicate that the mantra ‘lower is better’ applies not only to a single measurement but to lifetime exposure to LDL-C,” the editorialists write.
“I think treatment should be earlier than age 40,” Dr. Heidenreich said in an interview.
“Part of the reason that 40 was chosen as a threshold was because everyone looked at 10-year, or even 20-year risk, and thought there was no reason to worry until you get older. It’s interesting that we never accepted that with high blood pressure. But more and more, we are learning that it is a lifelong process,” he said.
“Statins are getting less and less expensive, and their safety is more and more established with every decade that goes by. I definitely agree with this paper that it would actually make sense to be starting much earlier for those with elevated CVD risk from their high cholesterol.”
The study was supported by the U.S. National Heart, Lung, and Blood Institute (NHLBI), the Medical Research Council, Swindon, U.K. Dr. Moran and Dr. Heidenreich have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Treating elevated low-density lipoprotein cholesterol (LDL-C) in adults younger than 40 with statins is highly cost-effective in men, and intermediately cost-effective in women, a new report suggests.
In a simulated model based on data from the U.S. National Health and Nutrition Examination Survey (NHANES), lipid lowering with statins or lifestyle interventions in this age group would prevent or reduce the risk of atherosclerotic cardiovascular disease (ASCVD) and improve quality of life in later years.
The findings were published online Nov. 8 in the Journal of the American College of Cardiology.
“My group does epidemiologic analyses with cohort studies as well as health economic analyses like this one, and if you have long-term longitudinal observation, you see that the early exposures are important for what happens later,” senior author Andrew E. Moran, MD, Columbia University Irving Medical Center, New York, told this news organization.
“But when it comes to treatment studies that a lot of the treatment guidelines are based on, those are usually short-term, and they usually enroll older people. We saw the gap in the evidence that this paper tries to fill,” Dr. Moran said.
His group used a computer simulation model to synthesize evidence from observational cohort studies and clinical trials of statin treatment, as well as health services data on the costs of medicines and treatments.
Combining information from these sources, the investigators made their best estimates of the potential health benefits and costs of treating high cholesterol earlier in life, compared with standard care, which was statin treatment at age 40, or if LDL-C was 190 mg/dL or greater.
Lipid lowering incremental to standard care with moderate-intensity statins or intensive lifestyle interventions was simulated starting when young adult LDL-C was either ≥160 mg/dL or ≥130 mg/dL.
They found that approximately 27% of young adults who are free of ASCVD have LDL-C ≥130 mg/dL, and 9% have LDL-C of ≥160 mg/dL.
Their model projected that treating adults younger than 40 with statins or lifestyle interventions would prevent lifetime ASCVD events and increase quality-adjusted life years (QALYs) compared with standard care, which would begin treatment at age 40.
Incremental cost-effectiveness ratios (ICERs) were $31,000/QALY for statin treatment in young adult men with LDL-C ≥130 mg/dL, and $106,000/QALY for statin treatment in young women with LDL-C ≥130 mg/dL.
Intensive lifestyle intervention was more costly and less effective than statin therapy.
“We are straining to find these young adults with very high cholesterol,” Dr. Moran noted. “A lot of young adults don’t even see a doctor. This is an argument for engaging them in their health care and getting them involved in some basic screening. Atherosclerosis is a long-term process that starts in childhood for a lot of people.”
More innovative approaches may be needed, because the traditional health care system is not doing a good job of reaching young adults, he added. “Many of them may not have adequate health insurance. They need health care in nontraditional ways; convenience is really important for them. Perhaps part of the solution here is to think about ways of reaching this particular group that is not engaged with health care generally.”
Time to relax the age 40 threshold
The U.S. Preventive Services Task Force and the American College of Cardiology/American Heart Association should emphasize lifetime risk of elevated cholesterol, Paul A. Heidenreich, MD, MS, Stanford University School of Medicine, California, and colleagues write in an accompanying editorial.
“In addition to calculating 10-year risk, we should calculate years of life lost (or QALYs lost) from unhealthy LDL-C levels, and both lifestyle and pharmacologic treatment should be considered to treat high LDL-C in adults regardless of age. We also need to communicate that the mantra ‘lower is better’ applies not only to a single measurement but to lifetime exposure to LDL-C,” the editorialists write.
“I think treatment should be earlier than age 40,” Dr. Heidenreich said in an interview.
“Part of the reason that 40 was chosen as a threshold was because everyone looked at 10-year, or even 20-year risk, and thought there was no reason to worry until you get older. It’s interesting that we never accepted that with high blood pressure. But more and more, we are learning that it is a lifelong process,” he said.
“Statins are getting less and less expensive, and their safety is more and more established with every decade that goes by. I definitely agree with this paper that it would actually make sense to be starting much earlier for those with elevated CVD risk from their high cholesterol.”
The study was supported by the U.S. National Heart, Lung, and Blood Institute (NHLBI), the Medical Research Council, Swindon, U.K. Dr. Moran and Dr. Heidenreich have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Treating elevated low-density lipoprotein cholesterol (LDL-C) in adults younger than 40 with statins is highly cost-effective in men, and intermediately cost-effective in women, a new report suggests.
In a simulated model based on data from the U.S. National Health and Nutrition Examination Survey (NHANES), lipid lowering with statins or lifestyle interventions in this age group would prevent or reduce the risk of atherosclerotic cardiovascular disease (ASCVD) and improve quality of life in later years.
The findings were published online Nov. 8 in the Journal of the American College of Cardiology.
“My group does epidemiologic analyses with cohort studies as well as health economic analyses like this one, and if you have long-term longitudinal observation, you see that the early exposures are important for what happens later,” senior author Andrew E. Moran, MD, Columbia University Irving Medical Center, New York, told this news organization.
“But when it comes to treatment studies that a lot of the treatment guidelines are based on, those are usually short-term, and they usually enroll older people. We saw the gap in the evidence that this paper tries to fill,” Dr. Moran said.
His group used a computer simulation model to synthesize evidence from observational cohort studies and clinical trials of statin treatment, as well as health services data on the costs of medicines and treatments.
Combining information from these sources, the investigators made their best estimates of the potential health benefits and costs of treating high cholesterol earlier in life, compared with standard care, which was statin treatment at age 40, or if LDL-C was 190 mg/dL or greater.
Lipid lowering incremental to standard care with moderate-intensity statins or intensive lifestyle interventions was simulated starting when young adult LDL-C was either ≥160 mg/dL or ≥130 mg/dL.
They found that approximately 27% of young adults who are free of ASCVD have LDL-C ≥130 mg/dL, and 9% have LDL-C of ≥160 mg/dL.
Their model projected that treating adults younger than 40 with statins or lifestyle interventions would prevent lifetime ASCVD events and increase quality-adjusted life years (QALYs) compared with standard care, which would begin treatment at age 40.
Incremental cost-effectiveness ratios (ICERs) were $31,000/QALY for statin treatment in young adult men with LDL-C ≥130 mg/dL, and $106,000/QALY for statin treatment in young women with LDL-C ≥130 mg/dL.
Intensive lifestyle intervention was more costly and less effective than statin therapy.
“We are straining to find these young adults with very high cholesterol,” Dr. Moran noted. “A lot of young adults don’t even see a doctor. This is an argument for engaging them in their health care and getting them involved in some basic screening. Atherosclerosis is a long-term process that starts in childhood for a lot of people.”
More innovative approaches may be needed, because the traditional health care system is not doing a good job of reaching young adults, he added. “Many of them may not have adequate health insurance. They need health care in nontraditional ways; convenience is really important for them. Perhaps part of the solution here is to think about ways of reaching this particular group that is not engaged with health care generally.”
Time to relax the age 40 threshold
The U.S. Preventive Services Task Force and the American College of Cardiology/American Heart Association should emphasize lifetime risk of elevated cholesterol, Paul A. Heidenreich, MD, MS, Stanford University School of Medicine, California, and colleagues write in an accompanying editorial.
“In addition to calculating 10-year risk, we should calculate years of life lost (or QALYs lost) from unhealthy LDL-C levels, and both lifestyle and pharmacologic treatment should be considered to treat high LDL-C in adults regardless of age. We also need to communicate that the mantra ‘lower is better’ applies not only to a single measurement but to lifetime exposure to LDL-C,” the editorialists write.
“I think treatment should be earlier than age 40,” Dr. Heidenreich said in an interview.
“Part of the reason that 40 was chosen as a threshold was because everyone looked at 10-year, or even 20-year risk, and thought there was no reason to worry until you get older. It’s interesting that we never accepted that with high blood pressure. But more and more, we are learning that it is a lifelong process,” he said.
“Statins are getting less and less expensive, and their safety is more and more established with every decade that goes by. I definitely agree with this paper that it would actually make sense to be starting much earlier for those with elevated CVD risk from their high cholesterol.”
The study was supported by the U.S. National Heart, Lung, and Blood Institute (NHLBI), the Medical Research Council, Swindon, U.K. Dr. Moran and Dr. Heidenreich have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.