Endocrinology

In the first revision to its guidance on the management of osteoporosis in a decade, the North American Menopause Society has issued an updated position statement addressing evolving evidence on osteoporosis issues ranging from screening and risk assessment to appropriate use of preventive therapy in postmenopausal women.

“Since the 2010 statement, there have been important new developments in our field, including better delineation of risk factors for fracture, resulting in better strategies for assessing fracture risk,” Michael R. McClung, MD, who is a NAMS board member and colead of the editorial panel for the 2021 position statement, told this news organization. Dr. McClung is also director emeritus of the Oregon Osteoporosis Center in Portland.

“There is much more information about the long-term safety of therapies,” he added. Dr. McClung also noted “the availability of four new drugs for the prevention and treatment of osteoporosis and clinical experience informing us of the effects of using different treatments in various sequences.”
 

Osteoporosis is substantially underdiagnosed and undertreated

A basis for the update, recently published in Menopause: The Journal of the North American Menopause Society, is the need to tackle the troubling fact that approximately half of postmenopausal women will experience a fracture related to osteoporosis in their lifetime, yet the condition is “substantially underdiagnosed and undertreated,” NAMS underscores.

With that in mind, osteoporosis should be considered by practitioners treating menopausal and postmenopausal women at all levels of care.

“All physicians and advanced care providers caring for postmenopausal women should be comfortable assessing and managing their patients with, or at risk for, fractures,” Dr. McClung added.
 

Osteoporosis prevention in young menopausal women

The NAMS statement covers a broad range of issues, and while most recommendations generally follow those of other societies’ guidelines, a unique aspect is the emphasis on preventing osteoporosis in young menopausal women with estrogen or other drugs.

While underscoring that all menopausal women should be encouraged to adopt healthy lifestyles, with good diets and physical activity to reduce the risk of bone loss and fractures, pharmacologic interventions also have a role, NAMS says.

Though long an issue of debate, NAMS voices support for estrogen therapy as having an important role in osteoporosis prevention, as estrogen deficiency is the principal cause of bone loss in postmenopausal women.

“Hormone therapy is the most appropriate choice to prevent bone loss at the time of menopause for healthy women, particularly those who have menopause symptoms,” the group states. Drug interventions are specifically supported in women with premature menopause, at least until the average age of natural menopause, in addition to those with low bone mineral density (BMD) (T-score < –1.0) and those experiencing relatively rapid bone loss related to acute estrogen deficiency in the menopause transition or on discontinuing estrogen therapy.

“Although using drugs to prevent osteoporosis is not included in national osteoporosis guidelines, a strong clinical argument can be made for doing so, especially in women who come to menopause with low bone mass,” the report states.

And therapy is also recommended if patients have a low BMD and other risk factors for fracture, such as family history, but do not meet the criteria for osteoporosis treatment.

Ultimately, clinicians should work with patients when deciding the options, Dr. McClung said. 

“After carefully weighing the small risks associated with hormone therapy or other therapies begun at the time of menopause, menopause practitioners and their patients can and should make informed decisions about the use of Food and Drug Administration–approved medications to prevent osteoporosis in women who are at risk for developing that condition,” he noted, adding that his view on the matter is his own and not necessarily that of NAMS.
 

New treatments endorsed for high-risk patients to avoid ‘bone attack’

While most patients are treated for osteoporosis with antiremodeling drugs such as bisphosphonates and denosumab, NAMS endorses “a new paradigm of beginning treatment with a bone-building agent followed by an antiremodeling agent” for women at very high risk of fracture.

“Consider osteoanabolic therapies for patients at very high risk of fracture, including older women with recent fractures, T-scores –3.0 and lower, or multiple other risk factors,” the statement suggests.

Among those at highest risk are women who have sustained a first fracture.

“A recent fracture in a postmenopausal woman is the strongest risk factor for another fracture,” Dr. McClung said.

In fact, “having a fracture should be thought of and assessed as a ‘bone attack,’ ” he asserted.

Therapy is recommended in such cases to rapidly increase bone density and reduce their subsequent fracture risk.

“For these patients, osteoanabolic or bone-building agents are more effective than bisphosphonates and are recommended as initial therapy,” Dr. McClung noted.

Treatment discontinuation?

On the issue of drug holidays and when or whether to stop therapy, as no therapies cure osteoporosis, medications should not be permanently stopped, even if bone density increases, NAMS recommends.

“By analogy, we do not stop diabetes therapy when A1c levels become normal,” Dr. McClung noted.

“Because the benefits of therapy on bone density and fracture protection wane, quickly for nonbisphosphonates and more slowly with bisphosphonates, short-term therapy, for instance 5 years, is not optimal treatment,” he said.

While the short-term interruption of bisphosphonate therapy may be considered in some patients, “the concept of ‘drug holidays’ does not pertain to nonbisphosphonate drugs,” Dr. McClung said.

NAMS adds that management of therapeutic choices should instead be ongoing.

“During therapy, reevaluate the treatment goals and the choice of medication on an ongoing basis through periodic medical examination and follow-up BMD testing,” NAMS recommends.

In terms of assessment, the measurement of bone mineral density while on treatment can gauge the current risk of fracture, and NAMS supports the use of the T-score at the hip as an appropriate clinical target in guiding choices of therapy.

Ultimately, “effective tools for diagnosing osteoporosis and assessing fracture risk are available, and well-studied strategies exist for managing bone health in women at both low and high risk of fracture,” NAMS concludes.

“By individualizing treatment approaches and monitoring and adjusting those approaches if the clinical picture changes, the consequences of osteoporosis on a menopausal woman’s activity and well-being can be minimized.”

Dr. McClung has reported receiving consulting fees from Amgen and Myovant, and honorarium for speaking from Amgen and Alexon. He serves on the boards of NAMS and the International Osteoporosis Foundation.

A version of this article first appeared on Medscape.com.

In the first revision to its guidance on the management of osteoporosis in a decade, the North American Menopause Society has issued an updated position statement addressing evolving evidence on osteoporosis issues ranging from screening and risk assessment to appropriate use of preventive therapy in postmenopausal women.

“Since the 2010 statement, there have been important new developments in our field, including better delineation of risk factors for fracture, resulting in better strategies for assessing fracture risk,” Michael R. McClung, MD, who is a NAMS board member and colead of the editorial panel for the 2021 position statement, told this news organization. Dr. McClung is also director emeritus of the Oregon Osteoporosis Center in Portland.

“There is much more information about the long-term safety of therapies,” he added. Dr. McClung also noted “the availability of four new drugs for the prevention and treatment of osteoporosis and clinical experience informing us of the effects of using different treatments in various sequences.”
 

Osteoporosis is substantially underdiagnosed and undertreated

A basis for the update, recently published in Menopause: The Journal of the North American Menopause Society, is the need to tackle the troubling fact that approximately half of postmenopausal women will experience a fracture related to osteoporosis in their lifetime, yet the condition is “substantially underdiagnosed and undertreated,” NAMS underscores.

With that in mind, osteoporosis should be considered by practitioners treating menopausal and postmenopausal women at all levels of care.

“All physicians and advanced care providers caring for postmenopausal women should be comfortable assessing and managing their patients with, or at risk for, fractures,” Dr. McClung added.
 

Osteoporosis prevention in young menopausal women

The NAMS statement covers a broad range of issues, and while most recommendations generally follow those of other societies’ guidelines, a unique aspect is the emphasis on preventing osteoporosis in young menopausal women with estrogen or other drugs.

While underscoring that all menopausal women should be encouraged to adopt healthy lifestyles, with good diets and physical activity to reduce the risk of bone loss and fractures, pharmacologic interventions also have a role, NAMS says.

Though long an issue of debate, NAMS voices support for estrogen therapy as having an important role in osteoporosis prevention, as estrogen deficiency is the principal cause of bone loss in postmenopausal women.

“Hormone therapy is the most appropriate choice to prevent bone loss at the time of menopause for healthy women, particularly those who have menopause symptoms,” the group states. Drug interventions are specifically supported in women with premature menopause, at least until the average age of natural menopause, in addition to those with low bone mineral density (BMD) (T-score < –1.0) and those experiencing relatively rapid bone loss related to acute estrogen deficiency in the menopause transition or on discontinuing estrogen therapy.

“Although using drugs to prevent osteoporosis is not included in national osteoporosis guidelines, a strong clinical argument can be made for doing so, especially in women who come to menopause with low bone mass,” the report states.

And therapy is also recommended if patients have a low BMD and other risk factors for fracture, such as family history, but do not meet the criteria for osteoporosis treatment.

Ultimately, clinicians should work with patients when deciding the options, Dr. McClung said. 

“After carefully weighing the small risks associated with hormone therapy or other therapies begun at the time of menopause, menopause practitioners and their patients can and should make informed decisions about the use of Food and Drug Administration–approved medications to prevent osteoporosis in women who are at risk for developing that condition,” he noted, adding that his view on the matter is his own and not necessarily that of NAMS.
 

New treatments endorsed for high-risk patients to avoid ‘bone attack’

While most patients are treated for osteoporosis with antiremodeling drugs such as bisphosphonates and denosumab, NAMS endorses “a new paradigm of beginning treatment with a bone-building agent followed by an antiremodeling agent” for women at very high risk of fracture.

“Consider osteoanabolic therapies for patients at very high risk of fracture, including older women with recent fractures, T-scores –3.0 and lower, or multiple other risk factors,” the statement suggests.

Among those at highest risk are women who have sustained a first fracture.

“A recent fracture in a postmenopausal woman is the strongest risk factor for another fracture,” Dr. McClung said.

In fact, “having a fracture should be thought of and assessed as a ‘bone attack,’ ” he asserted.

Therapy is recommended in such cases to rapidly increase bone density and reduce their subsequent fracture risk.

“For these patients, osteoanabolic or bone-building agents are more effective than bisphosphonates and are recommended as initial therapy,” Dr. McClung noted.

Treatment discontinuation?

On the issue of drug holidays and when or whether to stop therapy, as no therapies cure osteoporosis, medications should not be permanently stopped, even if bone density increases, NAMS recommends.

“By analogy, we do not stop diabetes therapy when A1c levels become normal,” Dr. McClung noted.

“Because the benefits of therapy on bone density and fracture protection wane, quickly for nonbisphosphonates and more slowly with bisphosphonates, short-term therapy, for instance 5 years, is not optimal treatment,” he said.

While the short-term interruption of bisphosphonate therapy may be considered in some patients, “the concept of ‘drug holidays’ does not pertain to nonbisphosphonate drugs,” Dr. McClung said.

NAMS adds that management of therapeutic choices should instead be ongoing.

“During therapy, reevaluate the treatment goals and the choice of medication on an ongoing basis through periodic medical examination and follow-up BMD testing,” NAMS recommends.

In terms of assessment, the measurement of bone mineral density while on treatment can gauge the current risk of fracture, and NAMS supports the use of the T-score at the hip as an appropriate clinical target in guiding choices of therapy.

Ultimately, “effective tools for diagnosing osteoporosis and assessing fracture risk are available, and well-studied strategies exist for managing bone health in women at both low and high risk of fracture,” NAMS concludes.

“By individualizing treatment approaches and monitoring and adjusting those approaches if the clinical picture changes, the consequences of osteoporosis on a menopausal woman’s activity and well-being can be minimized.”

Dr. McClung has reported receiving consulting fees from Amgen and Myovant, and honorarium for speaking from Amgen and Alexon. He serves on the boards of NAMS and the International Osteoporosis Foundation.

A version of this article first appeared on Medscape.com.

In the first revision to its guidance on the management of osteoporosis in a decade, the North American Menopause Society has issued an updated position statement addressing evolving evidence on osteoporosis issues ranging from screening and risk assessment to appropriate use of preventive therapy in postmenopausal women.

“Since the 2010 statement, there have been important new developments in our field, including better delineation of risk factors for fracture, resulting in better strategies for assessing fracture risk,” Michael R. McClung, MD, who is a NAMS board member and colead of the editorial panel for the 2021 position statement, told this news organization. Dr. McClung is also director emeritus of the Oregon Osteoporosis Center in Portland.

“There is much more information about the long-term safety of therapies,” he added. Dr. McClung also noted “the availability of four new drugs for the prevention and treatment of osteoporosis and clinical experience informing us of the effects of using different treatments in various sequences.”
 

Osteoporosis is substantially underdiagnosed and undertreated

A basis for the update, recently published in Menopause: The Journal of the North American Menopause Society, is the need to tackle the troubling fact that approximately half of postmenopausal women will experience a fracture related to osteoporosis in their lifetime, yet the condition is “substantially underdiagnosed and undertreated,” NAMS underscores.

With that in mind, osteoporosis should be considered by practitioners treating menopausal and postmenopausal women at all levels of care.

“All physicians and advanced care providers caring for postmenopausal women should be comfortable assessing and managing their patients with, or at risk for, fractures,” Dr. McClung added.
 

Osteoporosis prevention in young menopausal women

The NAMS statement covers a broad range of issues, and while most recommendations generally follow those of other societies’ guidelines, a unique aspect is the emphasis on preventing osteoporosis in young menopausal women with estrogen or other drugs.

While underscoring that all menopausal women should be encouraged to adopt healthy lifestyles, with good diets and physical activity to reduce the risk of bone loss and fractures, pharmacologic interventions also have a role, NAMS says.

Though long an issue of debate, NAMS voices support for estrogen therapy as having an important role in osteoporosis prevention, as estrogen deficiency is the principal cause of bone loss in postmenopausal women.

“Hormone therapy is the most appropriate choice to prevent bone loss at the time of menopause for healthy women, particularly those who have menopause symptoms,” the group states. Drug interventions are specifically supported in women with premature menopause, at least until the average age of natural menopause, in addition to those with low bone mineral density (BMD) (T-score < –1.0) and those experiencing relatively rapid bone loss related to acute estrogen deficiency in the menopause transition or on discontinuing estrogen therapy.

“Although using drugs to prevent osteoporosis is not included in national osteoporosis guidelines, a strong clinical argument can be made for doing so, especially in women who come to menopause with low bone mass,” the report states.

And therapy is also recommended if patients have a low BMD and other risk factors for fracture, such as family history, but do not meet the criteria for osteoporosis treatment.

Ultimately, clinicians should work with patients when deciding the options, Dr. McClung said. 

“After carefully weighing the small risks associated with hormone therapy or other therapies begun at the time of menopause, menopause practitioners and their patients can and should make informed decisions about the use of Food and Drug Administration–approved medications to prevent osteoporosis in women who are at risk for developing that condition,” he noted, adding that his view on the matter is his own and not necessarily that of NAMS.
 

New treatments endorsed for high-risk patients to avoid ‘bone attack’

While most patients are treated for osteoporosis with antiremodeling drugs such as bisphosphonates and denosumab, NAMS endorses “a new paradigm of beginning treatment with a bone-building agent followed by an antiremodeling agent” for women at very high risk of fracture.

“Consider osteoanabolic therapies for patients at very high risk of fracture, including older women with recent fractures, T-scores –3.0 and lower, or multiple other risk factors,” the statement suggests.

Among those at highest risk are women who have sustained a first fracture.

“A recent fracture in a postmenopausal woman is the strongest risk factor for another fracture,” Dr. McClung said.

In fact, “having a fracture should be thought of and assessed as a ‘bone attack,’ ” he asserted.

Therapy is recommended in such cases to rapidly increase bone density and reduce their subsequent fracture risk.

“For these patients, osteoanabolic or bone-building agents are more effective than bisphosphonates and are recommended as initial therapy,” Dr. McClung noted.

Treatment discontinuation?

On the issue of drug holidays and when or whether to stop therapy, as no therapies cure osteoporosis, medications should not be permanently stopped, even if bone density increases, NAMS recommends.

“By analogy, we do not stop diabetes therapy when A1c levels become normal,” Dr. McClung noted.

“Because the benefits of therapy on bone density and fracture protection wane, quickly for nonbisphosphonates and more slowly with bisphosphonates, short-term therapy, for instance 5 years, is not optimal treatment,” he said.

While the short-term interruption of bisphosphonate therapy may be considered in some patients, “the concept of ‘drug holidays’ does not pertain to nonbisphosphonate drugs,” Dr. McClung said.

NAMS adds that management of therapeutic choices should instead be ongoing.

“During therapy, reevaluate the treatment goals and the choice of medication on an ongoing basis through periodic medical examination and follow-up BMD testing,” NAMS recommends.

In terms of assessment, the measurement of bone mineral density while on treatment can gauge the current risk of fracture, and NAMS supports the use of the T-score at the hip as an appropriate clinical target in guiding choices of therapy.

Ultimately, “effective tools for diagnosing osteoporosis and assessing fracture risk are available, and well-studied strategies exist for managing bone health in women at both low and high risk of fracture,” NAMS concludes.

“By individualizing treatment approaches and monitoring and adjusting those approaches if the clinical picture changes, the consequences of osteoporosis on a menopausal woman’s activity and well-being can be minimized.”

Dr. McClung has reported receiving consulting fees from Amgen and Myovant, and honorarium for speaking from Amgen and Alexon. He serves on the boards of NAMS and the International Osteoporosis Foundation.

A version of this article first appeared on Medscape.com.

The SGLT2 inhibitor dapagliflozin scored a clear win in a randomized, controlled trial with more than 300 U.S. patients with heart failure with preserved ejection fraction (HFpEF), showing a significant and clinically meaningful benefit for the primary endpoint, a KCCQ measure of symptoms and physical limitations, after 12 weeks of treatment.

These results in the PRESERVED-HF study follow closely on the heals of the initial report from the EMPEROR-Preserved trial that showed a benefit from a different sodium-glucose cotransporter 2 (SGLT2) inhibitor, empagliflozin (Jardiance) in nearly 6,000 randomized patients for the primary endpoint of preventing cardiovascular death or hospitalizations for heart failure.

In PRESERVED-HF, patients with HFpEF who received a standard, once-daily dose of dapagliflozin (Farxiga) had an average 5.8-point improvement in their condition as measured by the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CS), the study’s primary endpoint.

This is “the first study to demonstrate that an SGLT2 inhibitor dapagliflozin significantly improves symptoms, physical limitations, and 6-minute walking distance in patients with HFpEF,” Mikhail N. Kosiborod, MD, reported at the annual scientific meeting of the Heart Failure Society of America. The secondary endpoint of 6-minute walking distance “has been very difficult to improve in many previous studies of other treatments” tested in patients with HFpEF, noted Dr. Kosiborod, a cardiologist and codirector of the Cardiometabolic Center of Excellence at Saint Luke’s Mid-America Heart Institute.

The results are “highly complementary” to the findings from large outcome trials, such as the findings from EMPEROR-Preserved, he said, and collectively the recent findings from these studies of SGLT2 inhibitors in patients with HFpEF identify drugs in this class as a “new treatment option” for patients with a disorder that until now had no treatment with unequivocally proven efficacy and safety.
 

‘Impressive and unprecedented’ findings

The findings are “really impressive and unprecedented,” said Milton Packer, MD, a cardiologist at Baylor University Medical Center in Dallas who was not involved in the study. “This is the largest KCCQ benefit ever seen in either patients with HFpEF or in patients with heart failure with reduced ejection fraction,” said Dr. Packer, one of the investigators who led the EMPEROR-Preserved trial.

MDedge News

PRESERVED-HF randomized 324 patients diagnosed with heart failure and with a left ventricular ejection fraction of 45% or higher at any of 26 U.S. centers, with 304 patients completing the planned final analysis after 12 weeks on treatment. Patients could be in New York Heart Association (NYHA) functional class II-IV, they had to have a baseline N-terminal pro-brain natriuretic peptide (NT-proBNP) level of at least 225 pg/mL (or higher if they also had atrial fibrillation), and they required at least one of three markers of established heart failure: recent hospitalization for heart failure or an urgent outpatient visit that required treatment with an IV diuretic, elevated filling pressure measured by left or right catheterization, or structural heart disease detected by echocardiography.

The average age of the enrolled patients was 70 years, and they had been diagnosed with heart failure for about 3 years; 57% were women, 30% were African American, and their median body mass index was 35 kg/m². Roughly 42% had NYHA class III or IV disease, 56% had type 2 diabetes, their median estimated glomerular filtration rate was about 55 mL/min per 1.73m², their median KCCQ-CS score at baseline was about 62, and their average 6-minute walk distance was 244 m.

These and other features of the enrolled population define a distinctly U.S. patient population, stressed Dr. Kosiborod, professor of medicine at the University of Missouri–Kansas City.

“The patients we enrolled are the patients we see in U.S. clinical practice,” he said in an interview. Importantly, the patient profile of a median BMI of 35 kg/m², a median KCCQ-CS score of 62 – “quite low,” noted Dr. Kosiborod – and having more than 40% of patients in NYHA functional class III defines a study population with a substantially greater burden of obesity, symptoms, and functional impairment compared with those enrolled in prior trials involving patients with HFpEF such as EMPEROR-Preserved.
 

Results complement findings from larger trials

PRESERVED-HF was an investigator-initiated study designed to inform clinical practice, not as a pivotal trial like EMPEROR-Preserved, which aims to gather evidence to support a new indication for regulatory approval. (On Sept. 9, 2021, the Food and Drug Administration granted empagliflozin “breakthrough therapy” status for treating HFpEF based on the EMPEROR-Preserved results, which will fast-track the agency’s decision on this indication.)

Dr. Kosiborod noted that he and his associates designed PRESERVED-HF with adequate patient numbers to power a statistically valid assessment of effect on KCCQ-CS score. While the new findings will not by themselves lead to a new indication for dapagliflozin to treat patients with HFpEF, they will potentially complement the pending results of another trial, DELIVER, by showing efficacy and safety in a uniquely U.S. patient population. DELIVER is a pivotal, global trial of dapagliflozin in more than 6,000 patients with HFpEF that’s on track to report findings in 2022.

Dr. Kosiborod also stressed that dapagliflozin has U.S.-approved indications for treating patients with type 2 diabetes, and for patients with chronic kidney disease, and that a majority of patients enrolled in PRESERVED-HF had one or both of these conditions. That makes the new findings especially compelling for patients with either type 2 diabetes or chronic kidney disease and HFpEF who are not already receiving an SGLT2 inhibitor.

Other findings that he reported showed a range of benefits consistent with the primary endpoint, including the KCCQ overall summary score, which also showed a significant 4.5-point average increase over placebo after 12 weeks. Analysis by the percentage of patients achieving at least a 5-point improvement in the KCCQ clinical summary score (the threshold for a clinically meaningful improvement) showed that about 45% of patients treated with dapagliflozin reached this mark compared with roughly 35% of patients in the placebo arm, indicating a number needed to treat of nine to have one additional patient achieve this threshold after 12 weeks. Average improvement in 6-minute walk distance was about 20 m with dapagliflozin compared with placebo.

No heterogeneity of effect by baseline ejection fraction.

Subgroup analyses showed no heterogeneity of response across 12 different ways of subdividing the study population, including age, sex, race, diabetes status, and BMI. The median left ventricular ejection fraction among enrolled patients was 60%, and the findings showed identical KCCQ improvements among patients with ejection fractions less than the median and those with an ejection fraction above the median.

This last finding was especially relevant because the EMPEROR-Preserved results showed a possible signal of heterogeneity by ejection fraction and an attenuated effect among patients with HFpEF and an ejection fraction above the 60%-65% range, although the certainty of this finding is currently controversial.

The impact of empagliflozin on KCCQ clinical summary score in EMPEROR-Preserved showed an average incremental improvement of 1.32 points compared with placebo, a significant difference, but more modest than the increment from dapagliflozin treatment seen in PRESERVED-HF. Dr. Kosiborod hypothesized that this difference might be mostly because of the different patient populations enrolled in the two studies.

Dr. Kosiborod noted that a report on the PRESERVED-HF results will soon appear in Nature Medicine.

PRESERVED-HF was funded by AstraZeneca, which markets dapagliflozin (Farxiga), but the trials’ design and conduct were independent of this funding source. Dr. Kosiborod has been a consultant to AstraZeneca and numerous other companies, and he has received research funding from AstraZeneca and Boehringer Ingelheim. Dr. Packer has had financial relationships with AstraZeneca and numerous other companies.

[email protected]

The SGLT2 inhibitor dapagliflozin scored a clear win in a randomized, controlled trial with more than 300 U.S. patients with heart failure with preserved ejection fraction (HFpEF), showing a significant and clinically meaningful benefit for the primary endpoint, a KCCQ measure of symptoms and physical limitations, after 12 weeks of treatment.

These results in the PRESERVED-HF study follow closely on the heals of the initial report from the EMPEROR-Preserved trial that showed a benefit from a different sodium-glucose cotransporter 2 (SGLT2) inhibitor, empagliflozin (Jardiance) in nearly 6,000 randomized patients for the primary endpoint of preventing cardiovascular death or hospitalizations for heart failure.

In PRESERVED-HF, patients with HFpEF who received a standard, once-daily dose of dapagliflozin (Farxiga) had an average 5.8-point improvement in their condition as measured by the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CS), the study’s primary endpoint.

This is “the first study to demonstrate that an SGLT2 inhibitor dapagliflozin significantly improves symptoms, physical limitations, and 6-minute walking distance in patients with HFpEF,” Mikhail N. Kosiborod, MD, reported at the annual scientific meeting of the Heart Failure Society of America. The secondary endpoint of 6-minute walking distance “has been very difficult to improve in many previous studies of other treatments” tested in patients with HFpEF, noted Dr. Kosiborod, a cardiologist and codirector of the Cardiometabolic Center of Excellence at Saint Luke’s Mid-America Heart Institute.

The results are “highly complementary” to the findings from large outcome trials, such as the findings from EMPEROR-Preserved, he said, and collectively the recent findings from these studies of SGLT2 inhibitors in patients with HFpEF identify drugs in this class as a “new treatment option” for patients with a disorder that until now had no treatment with unequivocally proven efficacy and safety.
 

‘Impressive and unprecedented’ findings

The findings are “really impressive and unprecedented,” said Milton Packer, MD, a cardiologist at Baylor University Medical Center in Dallas who was not involved in the study. “This is the largest KCCQ benefit ever seen in either patients with HFpEF or in patients with heart failure with reduced ejection fraction,” said Dr. Packer, one of the investigators who led the EMPEROR-Preserved trial.

MDedge News

PRESERVED-HF randomized 324 patients diagnosed with heart failure and with a left ventricular ejection fraction of 45% or higher at any of 26 U.S. centers, with 304 patients completing the planned final analysis after 12 weeks on treatment. Patients could be in New York Heart Association (NYHA) functional class II-IV, they had to have a baseline N-terminal pro-brain natriuretic peptide (NT-proBNP) level of at least 225 pg/mL (or higher if they also had atrial fibrillation), and they required at least one of three markers of established heart failure: recent hospitalization for heart failure or an urgent outpatient visit that required treatment with an IV diuretic, elevated filling pressure measured by left or right catheterization, or structural heart disease detected by echocardiography.

The average age of the enrolled patients was 70 years, and they had been diagnosed with heart failure for about 3 years; 57% were women, 30% were African American, and their median body mass index was 35 kg/m². Roughly 42% had NYHA class III or IV disease, 56% had type 2 diabetes, their median estimated glomerular filtration rate was about 55 mL/min per 1.73m², their median KCCQ-CS score at baseline was about 62, and their average 6-minute walk distance was 244 m.

These and other features of the enrolled population define a distinctly U.S. patient population, stressed Dr. Kosiborod, professor of medicine at the University of Missouri–Kansas City.

“The patients we enrolled are the patients we see in U.S. clinical practice,” he said in an interview. Importantly, the patient profile of a median BMI of 35 kg/m², a median KCCQ-CS score of 62 – “quite low,” noted Dr. Kosiborod – and having more than 40% of patients in NYHA functional class III defines a study population with a substantially greater burden of obesity, symptoms, and functional impairment compared with those enrolled in prior trials involving patients with HFpEF such as EMPEROR-Preserved.
 

Results complement findings from larger trials

PRESERVED-HF was an investigator-initiated study designed to inform clinical practice, not as a pivotal trial like EMPEROR-Preserved, which aims to gather evidence to support a new indication for regulatory approval. (On Sept. 9, 2021, the Food and Drug Administration granted empagliflozin “breakthrough therapy” status for treating HFpEF based on the EMPEROR-Preserved results, which will fast-track the agency’s decision on this indication.)

Dr. Kosiborod noted that he and his associates designed PRESERVED-HF with adequate patient numbers to power a statistically valid assessment of effect on KCCQ-CS score. While the new findings will not by themselves lead to a new indication for dapagliflozin to treat patients with HFpEF, they will potentially complement the pending results of another trial, DELIVER, by showing efficacy and safety in a uniquely U.S. patient population. DELIVER is a pivotal, global trial of dapagliflozin in more than 6,000 patients with HFpEF that’s on track to report findings in 2022.

Dr. Kosiborod also stressed that dapagliflozin has U.S.-approved indications for treating patients with type 2 diabetes, and for patients with chronic kidney disease, and that a majority of patients enrolled in PRESERVED-HF had one or both of these conditions. That makes the new findings especially compelling for patients with either type 2 diabetes or chronic kidney disease and HFpEF who are not already receiving an SGLT2 inhibitor.

Other findings that he reported showed a range of benefits consistent with the primary endpoint, including the KCCQ overall summary score, which also showed a significant 4.5-point average increase over placebo after 12 weeks. Analysis by the percentage of patients achieving at least a 5-point improvement in the KCCQ clinical summary score (the threshold for a clinically meaningful improvement) showed that about 45% of patients treated with dapagliflozin reached this mark compared with roughly 35% of patients in the placebo arm, indicating a number needed to treat of nine to have one additional patient achieve this threshold after 12 weeks. Average improvement in 6-minute walk distance was about 20 m with dapagliflozin compared with placebo.

No heterogeneity of effect by baseline ejection fraction.

Subgroup analyses showed no heterogeneity of response across 12 different ways of subdividing the study population, including age, sex, race, diabetes status, and BMI. The median left ventricular ejection fraction among enrolled patients was 60%, and the findings showed identical KCCQ improvements among patients with ejection fractions less than the median and those with an ejection fraction above the median.

This last finding was especially relevant because the EMPEROR-Preserved results showed a possible signal of heterogeneity by ejection fraction and an attenuated effect among patients with HFpEF and an ejection fraction above the 60%-65% range, although the certainty of this finding is currently controversial.

The impact of empagliflozin on KCCQ clinical summary score in EMPEROR-Preserved showed an average incremental improvement of 1.32 points compared with placebo, a significant difference, but more modest than the increment from dapagliflozin treatment seen in PRESERVED-HF. Dr. Kosiborod hypothesized that this difference might be mostly because of the different patient populations enrolled in the two studies.

Dr. Kosiborod noted that a report on the PRESERVED-HF results will soon appear in Nature Medicine.

PRESERVED-HF was funded by AstraZeneca, which markets dapagliflozin (Farxiga), but the trials’ design and conduct were independent of this funding source. Dr. Kosiborod has been a consultant to AstraZeneca and numerous other companies, and he has received research funding from AstraZeneca and Boehringer Ingelheim. Dr. Packer has had financial relationships with AstraZeneca and numerous other companies.

[email protected]

The SGLT2 inhibitor dapagliflozin scored a clear win in a randomized, controlled trial with more than 300 U.S. patients with heart failure with preserved ejection fraction (HFpEF), showing a significant and clinically meaningful benefit for the primary endpoint, a KCCQ measure of symptoms and physical limitations, after 12 weeks of treatment.

These results in the PRESERVED-HF study follow closely on the heals of the initial report from the EMPEROR-Preserved trial that showed a benefit from a different sodium-glucose cotransporter 2 (SGLT2) inhibitor, empagliflozin (Jardiance) in nearly 6,000 randomized patients for the primary endpoint of preventing cardiovascular death or hospitalizations for heart failure.

In PRESERVED-HF, patients with HFpEF who received a standard, once-daily dose of dapagliflozin (Farxiga) had an average 5.8-point improvement in their condition as measured by the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CS), the study’s primary endpoint.

This is “the first study to demonstrate that an SGLT2 inhibitor dapagliflozin significantly improves symptoms, physical limitations, and 6-minute walking distance in patients with HFpEF,” Mikhail N. Kosiborod, MD, reported at the annual scientific meeting of the Heart Failure Society of America. The secondary endpoint of 6-minute walking distance “has been very difficult to improve in many previous studies of other treatments” tested in patients with HFpEF, noted Dr. Kosiborod, a cardiologist and codirector of the Cardiometabolic Center of Excellence at Saint Luke’s Mid-America Heart Institute.

The results are “highly complementary” to the findings from large outcome trials, such as the findings from EMPEROR-Preserved, he said, and collectively the recent findings from these studies of SGLT2 inhibitors in patients with HFpEF identify drugs in this class as a “new treatment option” for patients with a disorder that until now had no treatment with unequivocally proven efficacy and safety.
 

‘Impressive and unprecedented’ findings

The findings are “really impressive and unprecedented,” said Milton Packer, MD, a cardiologist at Baylor University Medical Center in Dallas who was not involved in the study. “This is the largest KCCQ benefit ever seen in either patients with HFpEF or in patients with heart failure with reduced ejection fraction,” said Dr. Packer, one of the investigators who led the EMPEROR-Preserved trial.

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PRESERVED-HF randomized 324 patients diagnosed with heart failure and with a left ventricular ejection fraction of 45% or higher at any of 26 U.S. centers, with 304 patients completing the planned final analysis after 12 weeks on treatment. Patients could be in New York Heart Association (NYHA) functional class II-IV, they had to have a baseline N-terminal pro-brain natriuretic peptide (NT-proBNP) level of at least 225 pg/mL (or higher if they also had atrial fibrillation), and they required at least one of three markers of established heart failure: recent hospitalization for heart failure or an urgent outpatient visit that required treatment with an IV diuretic, elevated filling pressure measured by left or right catheterization, or structural heart disease detected by echocardiography.

The average age of the enrolled patients was 70 years, and they had been diagnosed with heart failure for about 3 years; 57% were women, 30% were African American, and their median body mass index was 35 kg/m². Roughly 42% had NYHA class III or IV disease, 56% had type 2 diabetes, their median estimated glomerular filtration rate was about 55 mL/min per 1.73m², their median KCCQ-CS score at baseline was about 62, and their average 6-minute walk distance was 244 m.

These and other features of the enrolled population define a distinctly U.S. patient population, stressed Dr. Kosiborod, professor of medicine at the University of Missouri–Kansas City.

“The patients we enrolled are the patients we see in U.S. clinical practice,” he said in an interview. Importantly, the patient profile of a median BMI of 35 kg/m², a median KCCQ-CS score of 62 – “quite low,” noted Dr. Kosiborod – and having more than 40% of patients in NYHA functional class III defines a study population with a substantially greater burden of obesity, symptoms, and functional impairment compared with those enrolled in prior trials involving patients with HFpEF such as EMPEROR-Preserved.
 

Results complement findings from larger trials

PRESERVED-HF was an investigator-initiated study designed to inform clinical practice, not as a pivotal trial like EMPEROR-Preserved, which aims to gather evidence to support a new indication for regulatory approval. (On Sept. 9, 2021, the Food and Drug Administration granted empagliflozin “breakthrough therapy” status for treating HFpEF based on the EMPEROR-Preserved results, which will fast-track the agency’s decision on this indication.)

Dr. Kosiborod noted that he and his associates designed PRESERVED-HF with adequate patient numbers to power a statistically valid assessment of effect on KCCQ-CS score. While the new findings will not by themselves lead to a new indication for dapagliflozin to treat patients with HFpEF, they will potentially complement the pending results of another trial, DELIVER, by showing efficacy and safety in a uniquely U.S. patient population. DELIVER is a pivotal, global trial of dapagliflozin in more than 6,000 patients with HFpEF that’s on track to report findings in 2022.

Dr. Kosiborod also stressed that dapagliflozin has U.S.-approved indications for treating patients with type 2 diabetes, and for patients with chronic kidney disease, and that a majority of patients enrolled in PRESERVED-HF had one or both of these conditions. That makes the new findings especially compelling for patients with either type 2 diabetes or chronic kidney disease and HFpEF who are not already receiving an SGLT2 inhibitor.

Other findings that he reported showed a range of benefits consistent with the primary endpoint, including the KCCQ overall summary score, which also showed a significant 4.5-point average increase over placebo after 12 weeks. Analysis by the percentage of patients achieving at least a 5-point improvement in the KCCQ clinical summary score (the threshold for a clinically meaningful improvement) showed that about 45% of patients treated with dapagliflozin reached this mark compared with roughly 35% of patients in the placebo arm, indicating a number needed to treat of nine to have one additional patient achieve this threshold after 12 weeks. Average improvement in 6-minute walk distance was about 20 m with dapagliflozin compared with placebo.

No heterogeneity of effect by baseline ejection fraction.

Subgroup analyses showed no heterogeneity of response across 12 different ways of subdividing the study population, including age, sex, race, diabetes status, and BMI. The median left ventricular ejection fraction among enrolled patients was 60%, and the findings showed identical KCCQ improvements among patients with ejection fractions less than the median and those with an ejection fraction above the median.

This last finding was especially relevant because the EMPEROR-Preserved results showed a possible signal of heterogeneity by ejection fraction and an attenuated effect among patients with HFpEF and an ejection fraction above the 60%-65% range, although the certainty of this finding is currently controversial.

The impact of empagliflozin on KCCQ clinical summary score in EMPEROR-Preserved showed an average incremental improvement of 1.32 points compared with placebo, a significant difference, but more modest than the increment from dapagliflozin treatment seen in PRESERVED-HF. Dr. Kosiborod hypothesized that this difference might be mostly because of the different patient populations enrolled in the two studies.

Dr. Kosiborod noted that a report on the PRESERVED-HF results will soon appear in Nature Medicine.

PRESERVED-HF was funded by AstraZeneca, which markets dapagliflozin (Farxiga), but the trials’ design and conduct were independent of this funding source. Dr. Kosiborod has been a consultant to AstraZeneca and numerous other companies, and he has received research funding from AstraZeneca and Boehringer Ingelheim. Dr. Packer has had financial relationships with AstraZeneca and numerous other companies.

[email protected]

At 18 months into the COVID-19 pandemic, many of the direct and indirect effects of SARS-CoV-2 on people with diabetes have become clearer, but knowledge gaps remain, say epidemiologists.

“COVID-19 has had a devastating effect on the population with diabetes, and conversely, the high prevalence of diabetes and uncontrolled diabetes has exacerbated the problem,” Edward W. Gregg, PhD, Imperial College London, lead author of a new literature review, told this news organization.

“As it becomes clear that the COVID-19 pandemic will be with us in different forms for the foreseeable future, the emphasis for people with diabetes needs to be continued primary care, glycemic management, and vaccination to reduce the long-term impact of COVID-19 in this population,” he added.

In data, mostly from case series, the review shows that more than one-third of people hospitalized with COVID-19 have diabetes. It is published in the September issue of Diabetes Care.

People with diabetes are more than three times as likely to be hospitalized for COVID-19 than those without diabetes, even after adjustment for age, sex, and other underlying conditions. Diabetes also accounts for 30%-40% of severe COVID-19 cases and deaths. Among those with diabetes hospitalized for COVID-19, 21%-43% require intensive care, and the case fatality rate is about 25%.

In one of the few multivariate analyses that examined type 1 and type 2 diabetes separately, conducted in the U.K., the odds of in-hospital COVID-19–related deaths, compared with people without diabetes, were almost three times higher (odds ratio, 2.9) for individuals with type 1 diabetes and almost twice as high (OR, 1.8) for those with type 2, after adjustment for comorbidities.

The causes of death appear to be a combination of factors specific to the SARS-CoV-2 infection and to diabetes-related factors, Dr. Gregg said in an interview.

“Much of the increased risk is due to the fact that people with diabetes have more comorbid factors, but there are many other mechanisms that appear to further increase risk, including the inflammatory and immune responses of people with diabetes, and hyperglycemia appears to have an exacerbating effect by itself.”
 

Elevated glucose is clear risk factor for COVID-19 severity

Elevated A1c was identified among several other overall predictors of poor COVID-19 outcomes, including obesity as well as comorbid kidney and cardiovascular disease.

High blood glucose levels at the time of admission in people with previously diagnosed or undiagnosed diabetes emerged as a clear predictor of worse outcomes. For example, among 605 people hospitalized with COVID-19 in China, those with fasting plasma glucose 6.1-6.9 mmol/L (110-125 mg/dL) and ≥7 mmol/L (126 mg/dL) had odds ratios of poor outcomes within 28 days of 2.6 and 4.0 compared with FPG <6.1 mmol/L (110 mg/dL).

Population-based studies in the U.K. found that A1c levels measured months before COVID-19 hospitalization were associated with risk for intensive care unit admission and/or death, particularly among those with type 1 diabetes. Overall, the death rate was 36% higher for those with A1c of 9%-9.9% versus 6.5%-7%.

Despite the link between high A1c and death, there is as yet no clear evidence that normalizing blood glucose levels minimizes COVID-19 severity, Dr. Gregg said.

“There are data that suggest poor glycemic control is associated with higher risk of poor outcomes. This is indirect evidence that managing blood sugar will help, but more direct evidence is needed.”
 

Evidence gaps identified

Dr. Gregg and co-authors Marisa Sophiea, PhD, MSc, and Misghina Weldegiorgis, PhD, BSc, also from Imperial College London, identify three areas in which more data are needed.

First, more information is needed to determine whether exposure, infection, and hospitalization risks differ by diabetes status and how those factors affect outcomes. The same studies would also be important to identify how factors such as behavior, masking, and lockdown policies, risk factor control, and household/community environments affect risk in people with diabetes.

Second, studies are needed to better understand indirect effects of the pandemic, such as care and management factors. Some of these, such as the advent of telehealth, may turn out to be beneficial in the long run, they note.

Finally, the pandemic has “brought a wealth of natural experiments,” such as how vaccination programs and other interventions are affecting people with diabetes specifically. Finally, population studies are needed in many parts of the world beyond the U.S. and the U.K., where most of that work has been done thus far.

“Many of the most important unanswered questions lie in the potential indirect and long-term impact of the pandemic that require population-based studies,” Dr. Gregg said. “Most of our knowledge so far is from case series, which only assess patients from the time of hospitalization.”

Indeed, very little data are available for people with diabetes who get COVID-19 but are not hospitalized, so it’s not known whether they have a longer duration of illness or are at greater risk for “long COVID” than those without diabetes who experience COVID-19 at home.

“I have not seen published data on this yet, and it’s an important unanswered question,” Dr. Gregg said.  

The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

At 18 months into the COVID-19 pandemic, many of the direct and indirect effects of SARS-CoV-2 on people with diabetes have become clearer, but knowledge gaps remain, say epidemiologists.

“COVID-19 has had a devastating effect on the population with diabetes, and conversely, the high prevalence of diabetes and uncontrolled diabetes has exacerbated the problem,” Edward W. Gregg, PhD, Imperial College London, lead author of a new literature review, told this news organization.

“As it becomes clear that the COVID-19 pandemic will be with us in different forms for the foreseeable future, the emphasis for people with diabetes needs to be continued primary care, glycemic management, and vaccination to reduce the long-term impact of COVID-19 in this population,” he added.

In data, mostly from case series, the review shows that more than one-third of people hospitalized with COVID-19 have diabetes. It is published in the September issue of Diabetes Care.

People with diabetes are more than three times as likely to be hospitalized for COVID-19 than those without diabetes, even after adjustment for age, sex, and other underlying conditions. Diabetes also accounts for 30%-40% of severe COVID-19 cases and deaths. Among those with diabetes hospitalized for COVID-19, 21%-43% require intensive care, and the case fatality rate is about 25%.

In one of the few multivariate analyses that examined type 1 and type 2 diabetes separately, conducted in the U.K., the odds of in-hospital COVID-19–related deaths, compared with people without diabetes, were almost three times higher (odds ratio, 2.9) for individuals with type 1 diabetes and almost twice as high (OR, 1.8) for those with type 2, after adjustment for comorbidities.

The causes of death appear to be a combination of factors specific to the SARS-CoV-2 infection and to diabetes-related factors, Dr. Gregg said in an interview.

“Much of the increased risk is due to the fact that people with diabetes have more comorbid factors, but there are many other mechanisms that appear to further increase risk, including the inflammatory and immune responses of people with diabetes, and hyperglycemia appears to have an exacerbating effect by itself.”
 

Elevated glucose is clear risk factor for COVID-19 severity

Elevated A1c was identified among several other overall predictors of poor COVID-19 outcomes, including obesity as well as comorbid kidney and cardiovascular disease.

High blood glucose levels at the time of admission in people with previously diagnosed or undiagnosed diabetes emerged as a clear predictor of worse outcomes. For example, among 605 people hospitalized with COVID-19 in China, those with fasting plasma glucose 6.1-6.9 mmol/L (110-125 mg/dL) and ≥7 mmol/L (126 mg/dL) had odds ratios of poor outcomes within 28 days of 2.6 and 4.0 compared with FPG <6.1 mmol/L (110 mg/dL).

Population-based studies in the U.K. found that A1c levels measured months before COVID-19 hospitalization were associated with risk for intensive care unit admission and/or death, particularly among those with type 1 diabetes. Overall, the death rate was 36% higher for those with A1c of 9%-9.9% versus 6.5%-7%.

Despite the link between high A1c and death, there is as yet no clear evidence that normalizing blood glucose levels minimizes COVID-19 severity, Dr. Gregg said.

“There are data that suggest poor glycemic control is associated with higher risk of poor outcomes. This is indirect evidence that managing blood sugar will help, but more direct evidence is needed.”
 

Evidence gaps identified

Dr. Gregg and co-authors Marisa Sophiea, PhD, MSc, and Misghina Weldegiorgis, PhD, BSc, also from Imperial College London, identify three areas in which more data are needed.

First, more information is needed to determine whether exposure, infection, and hospitalization risks differ by diabetes status and how those factors affect outcomes. The same studies would also be important to identify how factors such as behavior, masking, and lockdown policies, risk factor control, and household/community environments affect risk in people with diabetes.

Second, studies are needed to better understand indirect effects of the pandemic, such as care and management factors. Some of these, such as the advent of telehealth, may turn out to be beneficial in the long run, they note.

Finally, the pandemic has “brought a wealth of natural experiments,” such as how vaccination programs and other interventions are affecting people with diabetes specifically. Finally, population studies are needed in many parts of the world beyond the U.S. and the U.K., where most of that work has been done thus far.

“Many of the most important unanswered questions lie in the potential indirect and long-term impact of the pandemic that require population-based studies,” Dr. Gregg said. “Most of our knowledge so far is from case series, which only assess patients from the time of hospitalization.”

Indeed, very little data are available for people with diabetes who get COVID-19 but are not hospitalized, so it’s not known whether they have a longer duration of illness or are at greater risk for “long COVID” than those without diabetes who experience COVID-19 at home.

“I have not seen published data on this yet, and it’s an important unanswered question,” Dr. Gregg said.  

The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

At 18 months into the COVID-19 pandemic, many of the direct and indirect effects of SARS-CoV-2 on people with diabetes have become clearer, but knowledge gaps remain, say epidemiologists.

“COVID-19 has had a devastating effect on the population with diabetes, and conversely, the high prevalence of diabetes and uncontrolled diabetes has exacerbated the problem,” Edward W. Gregg, PhD, Imperial College London, lead author of a new literature review, told this news organization.

“As it becomes clear that the COVID-19 pandemic will be with us in different forms for the foreseeable future, the emphasis for people with diabetes needs to be continued primary care, glycemic management, and vaccination to reduce the long-term impact of COVID-19 in this population,” he added.

In data, mostly from case series, the review shows that more than one-third of people hospitalized with COVID-19 have diabetes. It is published in the September issue of Diabetes Care.

People with diabetes are more than three times as likely to be hospitalized for COVID-19 than those without diabetes, even after adjustment for age, sex, and other underlying conditions. Diabetes also accounts for 30%-40% of severe COVID-19 cases and deaths. Among those with diabetes hospitalized for COVID-19, 21%-43% require intensive care, and the case fatality rate is about 25%.

In one of the few multivariate analyses that examined type 1 and type 2 diabetes separately, conducted in the U.K., the odds of in-hospital COVID-19–related deaths, compared with people without diabetes, were almost three times higher (odds ratio, 2.9) for individuals with type 1 diabetes and almost twice as high (OR, 1.8) for those with type 2, after adjustment for comorbidities.

The causes of death appear to be a combination of factors specific to the SARS-CoV-2 infection and to diabetes-related factors, Dr. Gregg said in an interview.

“Much of the increased risk is due to the fact that people with diabetes have more comorbid factors, but there are many other mechanisms that appear to further increase risk, including the inflammatory and immune responses of people with diabetes, and hyperglycemia appears to have an exacerbating effect by itself.”
 

Elevated glucose is clear risk factor for COVID-19 severity

Elevated A1c was identified among several other overall predictors of poor COVID-19 outcomes, including obesity as well as comorbid kidney and cardiovascular disease.

High blood glucose levels at the time of admission in people with previously diagnosed or undiagnosed diabetes emerged as a clear predictor of worse outcomes. For example, among 605 people hospitalized with COVID-19 in China, those with fasting plasma glucose 6.1-6.9 mmol/L (110-125 mg/dL) and ≥7 mmol/L (126 mg/dL) had odds ratios of poor outcomes within 28 days of 2.6 and 4.0 compared with FPG <6.1 mmol/L (110 mg/dL).

Population-based studies in the U.K. found that A1c levels measured months before COVID-19 hospitalization were associated with risk for intensive care unit admission and/or death, particularly among those with type 1 diabetes. Overall, the death rate was 36% higher for those with A1c of 9%-9.9% versus 6.5%-7%.

Despite the link between high A1c and death, there is as yet no clear evidence that normalizing blood glucose levels minimizes COVID-19 severity, Dr. Gregg said.

“There are data that suggest poor glycemic control is associated with higher risk of poor outcomes. This is indirect evidence that managing blood sugar will help, but more direct evidence is needed.”
 

Evidence gaps identified

Dr. Gregg and co-authors Marisa Sophiea, PhD, MSc, and Misghina Weldegiorgis, PhD, BSc, also from Imperial College London, identify three areas in which more data are needed.

First, more information is needed to determine whether exposure, infection, and hospitalization risks differ by diabetes status and how those factors affect outcomes. The same studies would also be important to identify how factors such as behavior, masking, and lockdown policies, risk factor control, and household/community environments affect risk in people with diabetes.

Second, studies are needed to better understand indirect effects of the pandemic, such as care and management factors. Some of these, such as the advent of telehealth, may turn out to be beneficial in the long run, they note.

Finally, the pandemic has “brought a wealth of natural experiments,” such as how vaccination programs and other interventions are affecting people with diabetes specifically. Finally, population studies are needed in many parts of the world beyond the U.S. and the U.K., where most of that work has been done thus far.

“Many of the most important unanswered questions lie in the potential indirect and long-term impact of the pandemic that require population-based studies,” Dr. Gregg said. “Most of our knowledge so far is from case series, which only assess patients from the time of hospitalization.”

Indeed, very little data are available for people with diabetes who get COVID-19 but are not hospitalized, so it’s not known whether they have a longer duration of illness or are at greater risk for “long COVID” than those without diabetes who experience COVID-19 at home.

“I have not seen published data on this yet, and it’s an important unanswered question,” Dr. Gregg said.  

The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A “quadpill” containing quarter doses of four blood pressure (BP)–lowering medications was more effective than monotherapy for initial treatment of hypertension, with similar tolerability, in the 1-year, phase 3 QUARTET randomized, active-control trial.

ClaudioVentrella/Thinkstock

Clara Chow, MD, PhD, academic director of the Westmead Applied Research Centre, University of Sydney, presented the findings in a late-breaking trial session at the annual congress of the European Society of Cardiology. The study was simultaneously published in The Lancet.

The primary outcome, mean unattended office BP at 12 weeks, dropped from 142/86 mm Hg to 120/71 mm Hg in patients who received the daily quadpill – a capsule containing irbesartan, amlodipine, indapamide, and bisoprolol – and fell from 140/83 mm Hg to 127/79 mm Hg in patients who received a daily full dose of irbesartan.

This 6.9 mm Hg greater drop in systolic BP at 12 months is clinically meaningful, Dr. Chow told this news organization. “If maintained, it would be expected to confer about a 15%-20% reduction” in heart disease, stroke, and heart failure.

In the SPRINT study, she noted, the final systolic BP was 120 mm Hg in the intervention group and 134 mm Hg in the control group, and the difference was associated with a 27% reduction in the composite cardiovascular (CV) outcome.

The results of QUARTET suggest that, “even in those with stage 1 hypertension, we can safely reduce BP to a significant degree by this simple approach, compared to usual care,” Salim Yusuf, MD, DPhil, a long-time advocate of a polypill approach, said in an email.

Importantly, Dr. Chow pointed out, at 12 months, 81% of patients treated with the quadpill versus 62% of patients treated with monotherapy had BP control (<140/90 mm Hg). Patients who received monotherapy did not “catch up,” even though a higher percentage received stepped-up therapy.

The quadpill dosing strategy aligns with the latest 2018 ESC/European Society of Hypertension guidelines, which recommend starting antihypertensive treatment with more than one drug, session cochair Thomas Kahan, MD, PhD, Karolinska Institute, Danderyd Hospital, department of clinical sciences, Stockholm, commented.

“How many drugs should be in the initial step?” he asked. “Is four better than three or two, or should we have even more drugs at low doses?”

The trial was not designed to answer these questions, Dr. Chow replied. “We were really comparing [the quadpill] against what the majority of people around the planet are still doing, which is starting on one drug and slowly but surely stepping it up,” she said.

The quadpill was actually a capsule, she clarified, that contained four generic BP medications available in half doses in Australia. The half doses were cut in half and the medications were encapsulated. The control drug was prepared in an identical-looking capsule.  

It is important to note that “the time to BP control was shorter in patients who received the quadpill versus monotherapy,” session cochair Felix Mahfoud, MD, internal medicine and cardiology, Saarland University Hospital, Hamburg, Germany, pointed out, because “in clinical practice we aim to get patients to BP control as quickly as possible.”

“What is new here is the use of four drugs, each given at quarter doses,” Dr. Yusuf, director of the Population Health Research Institute, McMaster University, Hamilton, Ont., said. Although a few questions remain, “this study emphasizes the importance and potential benefits and simplicity of using combination BP-lowering drugs at low doses.”

For guidelines to be changed, he observed, the findings would have to be replicated in independent studies, and the quadpill would likely have to be shown to be superior to the dual pill.

“It took about 20 years [to change guidelines] after the first evidence that combinations of two pills were preferable to single-drug combinations,” he noted.

“I hope that in most people with elevated BP, at least a two-drug combination plus a statin plus aspirin will be prescribed,” Dr. Yusuf said. “This can reduce the risk of CVD events by 50% or more – a big impact both for the individual and for populations. The quad pill may have a role in this approach.”
 

Four-in-one pill

Worldwide, hypertension control is poor, Dr. Chow said, because of the need for multiple medications, treatment inertia, and concerns about adverse events.

The researchers hypothesized that initial antihypertensive treatment with a four-in-one pill with quarter doses of each medication would minimize side effects, maximize BP lowering, and overcome these treatment barriers and concerns. A pilot study of this strategy published by the group in 2017 showed promise.

QUARTET randomized 591 adults with hypertension, seen at clinics in four states in Australia from June 2017 through August 2020.  

Patients were either receiving no antihypertensive medication and had an unattended standard office BP of 140/90 to 179/109 mm Hg or daytime ambulatory BP greater than 135/95 mm Hg, or they were on BP-lowering monotherapy and had a BP of 130/85 to 179/109 mm Hg or daytime ambulatory BP greater than 125/80 mm Hg. Patients who were taking antihypertensive therapy entered a washout period before the trial.

The researchers randomized 291 participants to receive 150 mg irbesartan daily (usual care or control group).

The other 300 participants received a daily quadpill containing 37.5 mg irbesartan, 1.25 mg amlodipine, 0.625 mg indapamide, and 2.5 mg bisoprolol. The first three drugs are the most commonly prescribed angiotensin II receptor blocker, calcium channel blocker, and thiazide or thiazidelike diuretic in Australia, and the last drug, a beta-blocker, has a long duration of action, the study protocol explains.

Patients in both groups had similar baseline characteristics. They were a mean age of 58 years, 40% were women, and 82% were White. They also had a mean body mass index of 31 kg/m². About 8% were current smokers, and about 54% were not taking a BP-lowering drug.

Participants had clinic visits at baseline, 6 weeks, and 12 weeks, and if they continued the study, at 26 weeks and 52 weeks.

If a patient’s blood pressure was higher than 140/90 mm Hg, clinicians could add another medication, starting with amlodipine 5 mg.

At 12 weeks, 15% of patients in the intervention group and 40% in the control group had stepped up treatment.

Despite greater up-titration in the usual care group, BP control remained higher in the quadpill group, Dr. Chow pointed out. That is, patients in the quadpill group were more likely than patients in the usual care group to have a BP less than 140/90 mm Hg (76% vs. 58% respectively; P < .0001).

Patients in the quadpill group also had lower daytime and nighttime ambulatory systolic BP.

At 12 months, among the 417 patients who continued treatment, patients in the quadpill group had a 7.7 mm Hg greater drop in systolic BP, compared with patients in the control group, (P < .001).  

There were no significant differences in adverse events, which were most commonly dizziness (31% and 25%) or muscle cramps, gastrointestinal complaints, headache, or musculoskeletal complaints.

At 12 weeks, there were seven serious adverse events in the intervention group versus three in the control group. There were 12 treatment withdrawals in the intervention group versus seven in the control group (P = .27).

Remaining questions, upcoming phase 3 U.S. study

“While the [QUARTET] results are impressive, we are left with a number of questions,” Dr. Yusuf said.

Would the results be the same with a three-drug combo or even a two-drug combo at half doses? In the HOPE 3 trial, a two-drug combo at half doses provided similar results to the current study, over a much longer mean follow-up of 5.6 years, he noted.

Also, is the quadpill associated with higher rates of diabetes or higher creatinine levels in the long term? “Given that we do not have any data on long-term clinical outcomes from a four-drug combination,” Dr. Yusuf said, “caution should be utilized.”

Would the reduced risk of CVD be greater with a combination of low doses of two BP-lowering drugs plus a statin plus aspirin? That may be superior, he said, “based on recent information published on the polypill indicating a 50% relative risk reduction in CVD events.”

The related phase 2 QUARTET US trial should shed further light on a quadpill strategy. Patients with hypertension are being randomized to a daily quadpill containing 2 mg candesartan, 1.25 mg amlodipine besylate, 0.625 mg indapamide, and 2.5 mg bisoprolol, or to usual care, 8 mg candesartan daily.

Investigators plan to enroll 87 participants in the Chicago area, with estimated study completion by March 31, 2023.

The study was supported by an Australian National Health and Medical Research Council grant. The George Institute for Global Health has submitted patent applications for low–fixed-dose combination products to treat CV or cardiometabolic disease. Dr. Chow and coauthor Kris Rogers, PhD, senior biostatistician at The George Institute for Global Health, Newtown, Australia, are listed as inventors, but they do not have direct financial interests in these patent applications.

A version of this article first appeared on Medscape.com.

A “quadpill” containing quarter doses of four blood pressure (BP)–lowering medications was more effective than monotherapy for initial treatment of hypertension, with similar tolerability, in the 1-year, phase 3 QUARTET randomized, active-control trial.

ClaudioVentrella/Thinkstock

Clara Chow, MD, PhD, academic director of the Westmead Applied Research Centre, University of Sydney, presented the findings in a late-breaking trial session at the annual congress of the European Society of Cardiology. The study was simultaneously published in The Lancet.

The primary outcome, mean unattended office BP at 12 weeks, dropped from 142/86 mm Hg to 120/71 mm Hg in patients who received the daily quadpill – a capsule containing irbesartan, amlodipine, indapamide, and bisoprolol – and fell from 140/83 mm Hg to 127/79 mm Hg in patients who received a daily full dose of irbesartan.

This 6.9 mm Hg greater drop in systolic BP at 12 months is clinically meaningful, Dr. Chow told this news organization. “If maintained, it would be expected to confer about a 15%-20% reduction” in heart disease, stroke, and heart failure.

In the SPRINT study, she noted, the final systolic BP was 120 mm Hg in the intervention group and 134 mm Hg in the control group, and the difference was associated with a 27% reduction in the composite cardiovascular (CV) outcome.

The results of QUARTET suggest that, “even in those with stage 1 hypertension, we can safely reduce BP to a significant degree by this simple approach, compared to usual care,” Salim Yusuf, MD, DPhil, a long-time advocate of a polypill approach, said in an email.

Importantly, Dr. Chow pointed out, at 12 months, 81% of patients treated with the quadpill versus 62% of patients treated with monotherapy had BP control (<140/90 mm Hg). Patients who received monotherapy did not “catch up,” even though a higher percentage received stepped-up therapy.

The quadpill dosing strategy aligns with the latest 2018 ESC/European Society of Hypertension guidelines, which recommend starting antihypertensive treatment with more than one drug, session cochair Thomas Kahan, MD, PhD, Karolinska Institute, Danderyd Hospital, department of clinical sciences, Stockholm, commented.

“How many drugs should be in the initial step?” he asked. “Is four better than three or two, or should we have even more drugs at low doses?”

The trial was not designed to answer these questions, Dr. Chow replied. “We were really comparing [the quadpill] against what the majority of people around the planet are still doing, which is starting on one drug and slowly but surely stepping it up,” she said.

The quadpill was actually a capsule, she clarified, that contained four generic BP medications available in half doses in Australia. The half doses were cut in half and the medications were encapsulated. The control drug was prepared in an identical-looking capsule.  

It is important to note that “the time to BP control was shorter in patients who received the quadpill versus monotherapy,” session cochair Felix Mahfoud, MD, internal medicine and cardiology, Saarland University Hospital, Hamburg, Germany, pointed out, because “in clinical practice we aim to get patients to BP control as quickly as possible.”

“What is new here is the use of four drugs, each given at quarter doses,” Dr. Yusuf, director of the Population Health Research Institute, McMaster University, Hamilton, Ont., said. Although a few questions remain, “this study emphasizes the importance and potential benefits and simplicity of using combination BP-lowering drugs at low doses.”

For guidelines to be changed, he observed, the findings would have to be replicated in independent studies, and the quadpill would likely have to be shown to be superior to the dual pill.

“It took about 20 years [to change guidelines] after the first evidence that combinations of two pills were preferable to single-drug combinations,” he noted.

“I hope that in most people with elevated BP, at least a two-drug combination plus a statin plus aspirin will be prescribed,” Dr. Yusuf said. “This can reduce the risk of CVD events by 50% or more – a big impact both for the individual and for populations. The quad pill may have a role in this approach.”
 

Four-in-one pill

Worldwide, hypertension control is poor, Dr. Chow said, because of the need for multiple medications, treatment inertia, and concerns about adverse events.

The researchers hypothesized that initial antihypertensive treatment with a four-in-one pill with quarter doses of each medication would minimize side effects, maximize BP lowering, and overcome these treatment barriers and concerns. A pilot study of this strategy published by the group in 2017 showed promise.

QUARTET randomized 591 adults with hypertension, seen at clinics in four states in Australia from June 2017 through August 2020.  

Patients were either receiving no antihypertensive medication and had an unattended standard office BP of 140/90 to 179/109 mm Hg or daytime ambulatory BP greater than 135/95 mm Hg, or they were on BP-lowering monotherapy and had a BP of 130/85 to 179/109 mm Hg or daytime ambulatory BP greater than 125/80 mm Hg. Patients who were taking antihypertensive therapy entered a washout period before the trial.

The researchers randomized 291 participants to receive 150 mg irbesartan daily (usual care or control group).

The other 300 participants received a daily quadpill containing 37.5 mg irbesartan, 1.25 mg amlodipine, 0.625 mg indapamide, and 2.5 mg bisoprolol. The first three drugs are the most commonly prescribed angiotensin II receptor blocker, calcium channel blocker, and thiazide or thiazidelike diuretic in Australia, and the last drug, a beta-blocker, has a long duration of action, the study protocol explains.

Patients in both groups had similar baseline characteristics. They were a mean age of 58 years, 40% were women, and 82% were White. They also had a mean body mass index of 31 kg/m². About 8% were current smokers, and about 54% were not taking a BP-lowering drug.

Participants had clinic visits at baseline, 6 weeks, and 12 weeks, and if they continued the study, at 26 weeks and 52 weeks.

If a patient’s blood pressure was higher than 140/90 mm Hg, clinicians could add another medication, starting with amlodipine 5 mg.

At 12 weeks, 15% of patients in the intervention group and 40% in the control group had stepped up treatment.

Despite greater up-titration in the usual care group, BP control remained higher in the quadpill group, Dr. Chow pointed out. That is, patients in the quadpill group were more likely than patients in the usual care group to have a BP less than 140/90 mm Hg (76% vs. 58% respectively; P < .0001).

Patients in the quadpill group also had lower daytime and nighttime ambulatory systolic BP.

At 12 months, among the 417 patients who continued treatment, patients in the quadpill group had a 7.7 mm Hg greater drop in systolic BP, compared with patients in the control group, (P < .001).  

There were no significant differences in adverse events, which were most commonly dizziness (31% and 25%) or muscle cramps, gastrointestinal complaints, headache, or musculoskeletal complaints.

At 12 weeks, there were seven serious adverse events in the intervention group versus three in the control group. There were 12 treatment withdrawals in the intervention group versus seven in the control group (P = .27).

Remaining questions, upcoming phase 3 U.S. study

“While the [QUARTET] results are impressive, we are left with a number of questions,” Dr. Yusuf said.

Would the results be the same with a three-drug combo or even a two-drug combo at half doses? In the HOPE 3 trial, a two-drug combo at half doses provided similar results to the current study, over a much longer mean follow-up of 5.6 years, he noted.

Also, is the quadpill associated with higher rates of diabetes or higher creatinine levels in the long term? “Given that we do not have any data on long-term clinical outcomes from a four-drug combination,” Dr. Yusuf said, “caution should be utilized.”

Would the reduced risk of CVD be greater with a combination of low doses of two BP-lowering drugs plus a statin plus aspirin? That may be superior, he said, “based on recent information published on the polypill indicating a 50% relative risk reduction in CVD events.”

The related phase 2 QUARTET US trial should shed further light on a quadpill strategy. Patients with hypertension are being randomized to a daily quadpill containing 2 mg candesartan, 1.25 mg amlodipine besylate, 0.625 mg indapamide, and 2.5 mg bisoprolol, or to usual care, 8 mg candesartan daily.

Investigators plan to enroll 87 participants in the Chicago area, with estimated study completion by March 31, 2023.

The study was supported by an Australian National Health and Medical Research Council grant. The George Institute for Global Health has submitted patent applications for low–fixed-dose combination products to treat CV or cardiometabolic disease. Dr. Chow and coauthor Kris Rogers, PhD, senior biostatistician at The George Institute for Global Health, Newtown, Australia, are listed as inventors, but they do not have direct financial interests in these patent applications.

A version of this article first appeared on Medscape.com.

A “quadpill” containing quarter doses of four blood pressure (BP)–lowering medications was more effective than monotherapy for initial treatment of hypertension, with similar tolerability, in the 1-year, phase 3 QUARTET randomized, active-control trial.

ClaudioVentrella/Thinkstock

Clara Chow, MD, PhD, academic director of the Westmead Applied Research Centre, University of Sydney, presented the findings in a late-breaking trial session at the annual congress of the European Society of Cardiology. The study was simultaneously published in The Lancet.

The primary outcome, mean unattended office BP at 12 weeks, dropped from 142/86 mm Hg to 120/71 mm Hg in patients who received the daily quadpill – a capsule containing irbesartan, amlodipine, indapamide, and bisoprolol – and fell from 140/83 mm Hg to 127/79 mm Hg in patients who received a daily full dose of irbesartan.

This 6.9 mm Hg greater drop in systolic BP at 12 months is clinically meaningful, Dr. Chow told this news organization. “If maintained, it would be expected to confer about a 15%-20% reduction” in heart disease, stroke, and heart failure.

In the SPRINT study, she noted, the final systolic BP was 120 mm Hg in the intervention group and 134 mm Hg in the control group, and the difference was associated with a 27% reduction in the composite cardiovascular (CV) outcome.

The results of QUARTET suggest that, “even in those with stage 1 hypertension, we can safely reduce BP to a significant degree by this simple approach, compared to usual care,” Salim Yusuf, MD, DPhil, a long-time advocate of a polypill approach, said in an email.

Importantly, Dr. Chow pointed out, at 12 months, 81% of patients treated with the quadpill versus 62% of patients treated with monotherapy had BP control (<140/90 mm Hg). Patients who received monotherapy did not “catch up,” even though a higher percentage received stepped-up therapy.

The quadpill dosing strategy aligns with the latest 2018 ESC/European Society of Hypertension guidelines, which recommend starting antihypertensive treatment with more than one drug, session cochair Thomas Kahan, MD, PhD, Karolinska Institute, Danderyd Hospital, department of clinical sciences, Stockholm, commented.

“How many drugs should be in the initial step?” he asked. “Is four better than three or two, or should we have even more drugs at low doses?”

The trial was not designed to answer these questions, Dr. Chow replied. “We were really comparing [the quadpill] against what the majority of people around the planet are still doing, which is starting on one drug and slowly but surely stepping it up,” she said.

The quadpill was actually a capsule, she clarified, that contained four generic BP medications available in half doses in Australia. The half doses were cut in half and the medications were encapsulated. The control drug was prepared in an identical-looking capsule.  

It is important to note that “the time to BP control was shorter in patients who received the quadpill versus monotherapy,” session cochair Felix Mahfoud, MD, internal medicine and cardiology, Saarland University Hospital, Hamburg, Germany, pointed out, because “in clinical practice we aim to get patients to BP control as quickly as possible.”

“What is new here is the use of four drugs, each given at quarter doses,” Dr. Yusuf, director of the Population Health Research Institute, McMaster University, Hamilton, Ont., said. Although a few questions remain, “this study emphasizes the importance and potential benefits and simplicity of using combination BP-lowering drugs at low doses.”

For guidelines to be changed, he observed, the findings would have to be replicated in independent studies, and the quadpill would likely have to be shown to be superior to the dual pill.

“It took about 20 years [to change guidelines] after the first evidence that combinations of two pills were preferable to single-drug combinations,” he noted.

“I hope that in most people with elevated BP, at least a two-drug combination plus a statin plus aspirin will be prescribed,” Dr. Yusuf said. “This can reduce the risk of CVD events by 50% or more – a big impact both for the individual and for populations. The quad pill may have a role in this approach.”
 

Four-in-one pill

Worldwide, hypertension control is poor, Dr. Chow said, because of the need for multiple medications, treatment inertia, and concerns about adverse events.

The researchers hypothesized that initial antihypertensive treatment with a four-in-one pill with quarter doses of each medication would minimize side effects, maximize BP lowering, and overcome these treatment barriers and concerns. A pilot study of this strategy published by the group in 2017 showed promise.

QUARTET randomized 591 adults with hypertension, seen at clinics in four states in Australia from June 2017 through August 2020.  

Patients were either receiving no antihypertensive medication and had an unattended standard office BP of 140/90 to 179/109 mm Hg or daytime ambulatory BP greater than 135/95 mm Hg, or they were on BP-lowering monotherapy and had a BP of 130/85 to 179/109 mm Hg or daytime ambulatory BP greater than 125/80 mm Hg. Patients who were taking antihypertensive therapy entered a washout period before the trial.

The researchers randomized 291 participants to receive 150 mg irbesartan daily (usual care or control group).

The other 300 participants received a daily quadpill containing 37.5 mg irbesartan, 1.25 mg amlodipine, 0.625 mg indapamide, and 2.5 mg bisoprolol. The first three drugs are the most commonly prescribed angiotensin II receptor blocker, calcium channel blocker, and thiazide or thiazidelike diuretic in Australia, and the last drug, a beta-blocker, has a long duration of action, the study protocol explains.

Patients in both groups had similar baseline characteristics. They were a mean age of 58 years, 40% were women, and 82% were White. They also had a mean body mass index of 31 kg/m². About 8% were current smokers, and about 54% were not taking a BP-lowering drug.

Participants had clinic visits at baseline, 6 weeks, and 12 weeks, and if they continued the study, at 26 weeks and 52 weeks.

If a patient’s blood pressure was higher than 140/90 mm Hg, clinicians could add another medication, starting with amlodipine 5 mg.

At 12 weeks, 15% of patients in the intervention group and 40% in the control group had stepped up treatment.

Despite greater up-titration in the usual care group, BP control remained higher in the quadpill group, Dr. Chow pointed out. That is, patients in the quadpill group were more likely than patients in the usual care group to have a BP less than 140/90 mm Hg (76% vs. 58% respectively; P < .0001).

Patients in the quadpill group also had lower daytime and nighttime ambulatory systolic BP.

At 12 months, among the 417 patients who continued treatment, patients in the quadpill group had a 7.7 mm Hg greater drop in systolic BP, compared with patients in the control group, (P < .001).  

There were no significant differences in adverse events, which were most commonly dizziness (31% and 25%) or muscle cramps, gastrointestinal complaints, headache, or musculoskeletal complaints.

At 12 weeks, there were seven serious adverse events in the intervention group versus three in the control group. There were 12 treatment withdrawals in the intervention group versus seven in the control group (P = .27).

Remaining questions, upcoming phase 3 U.S. study

“While the [QUARTET] results are impressive, we are left with a number of questions,” Dr. Yusuf said.

Would the results be the same with a three-drug combo or even a two-drug combo at half doses? In the HOPE 3 trial, a two-drug combo at half doses provided similar results to the current study, over a much longer mean follow-up of 5.6 years, he noted.

Also, is the quadpill associated with higher rates of diabetes or higher creatinine levels in the long term? “Given that we do not have any data on long-term clinical outcomes from a four-drug combination,” Dr. Yusuf said, “caution should be utilized.”

Would the reduced risk of CVD be greater with a combination of low doses of two BP-lowering drugs plus a statin plus aspirin? That may be superior, he said, “based on recent information published on the polypill indicating a 50% relative risk reduction in CVD events.”

The related phase 2 QUARTET US trial should shed further light on a quadpill strategy. Patients with hypertension are being randomized to a daily quadpill containing 2 mg candesartan, 1.25 mg amlodipine besylate, 0.625 mg indapamide, and 2.5 mg bisoprolol, or to usual care, 8 mg candesartan daily.

Investigators plan to enroll 87 participants in the Chicago area, with estimated study completion by March 31, 2023.

The study was supported by an Australian National Health and Medical Research Council grant. The George Institute for Global Health has submitted patent applications for low–fixed-dose combination products to treat CV or cardiometabolic disease. Dr. Chow and coauthor Kris Rogers, PhD, senior biostatistician at The George Institute for Global Health, Newtown, Australia, are listed as inventors, but they do not have direct financial interests in these patent applications.

A version of this article first appeared on Medscape.com.

Basing referral of patients with chronic kidney disease (CKD) to nephrologists on 2-year kidney failure risk exceeding 1% would catch those at higher risk without increasing referral volumes generated from current laboratory-based guidelines, new research indicates.

And combining the two methods – predicted kidney failure risk with lab values – will lead to better patient outcomes by pinpointing CKD patients who most need specialty care, said study author Vishal Duggal, MD, who was a postdoctoral fellow in medical informatics at the Veterans Affairs Palo Alto (Calif.) Health Care System while conducting the research.

“We hope this can provide guidance to primary care physicians and nephrologists to give context for their decision-making,” Dr. Duggal told this news organization.

The VA is the largest provider of CKD care in the United States, developing clinical practice guidelines for CKD management that include suggested indications for nephrology referral based on laboratory values. Laboratory values that are typically used to guide referral include estimated glomerular filtration rate (eGFR) and its rate of decline per year, as well as heavy proteinuria in patients with and without diabetes. 

Dr. Duggal and colleagues – who published their findings in the American Journal of Kidney Diseases – conducted a retrospective analysis of nearly 400,000 veterans with CKD over a yearlong period to determine if referral volume would change if it was based on the estimated risk for kidney failure, rather than solely using laboratory values.

They also estimated the potential volume of nephrology referrals based on a combination of both estimated risk for kidney failure and laboratory data.

Kidney failure risk was calculated using an electronic clinical decision support tool, called Kidney Failure Risk Equation incorporating age, eGFR, gender, and urine albumin-to-creatinine ratio.
 

Targeting fewer patients to specialty care

Among all participants with CKD not already receiving nephrology care, more than 150,000 (41.5%) had a urine albumin or protein measurement leading to computable risk for end-stage kidney disease.

More than 66,200 patients met actual laboratory indications for referral but had not previously seen a nephrologist. Among these patients, 11,752 (17.7%) were referred to nephrology in the following year, and all had a median 2-year predicted risk for kidney failure of 1.5%.

Referred patients were more likely to meet several potential referral criteria, especially eGFR less than 30 mL/min per 1.73 m² and heavy proteinuria. Those with heavy proteinuria with diabetes, or the eGFR indication, had the highest predicted risk for kidney failure at 2 years, at 10% and 7.1% respectively.

Boosting referral volume can be problematic if patients aren’t prioritized by need, Dr. Duggal said, noting that many reasons explain why fewer than one in five CKD patients meeting lab indications for referral aren’t actually referred.

This can include patient preference, he noted: “Kidney disease is a disease of aging, and some patients don’t want to see a specialist or escalate their care.”

“Also, not everyone who has CKD is recommended to see a nephrologist, since primary care physicians do manage a lot of CKD as well.”

Basing referral on predicted kidney failure risk alone, a 2-year risk threshold of at least 1%, would identify a comparable number of patients (n = 72,948) as laboratory-based criteria, the team found, although they note that the patients identified using the KFRE tool would be at higher risk than those identified by lab values alone.

But when they combined the two – a minimum kidney failure risk of at least 1% over 2 years being applied to all new patients meeting lab-based referral indications, those pinpointed for nephrology referral dropped by 42.3%, from 66,276 to an estimated 38,229 patients.

“The current guidelines that just incorporate lab values identify a significant number of patients who are at low risk of developing end-stage kidney disease (ESKD), so incorporating kidney failure risk into current guidelines would target fewer patients to get to specialty care,” Dr. Duggal explained.
 

KFRE tool can be found online

Dr. Duggal emphasized that his findings do not change nephrology referral guidelines, but said physicians can find the KFRE tool online and use it to supplement their decision-making about a patient’s care.

“Further incorporating this [kidney failure] risk into referral practices might highlight a patient at extremely high risk who would benefit more from an interdisciplinary care team,” he said.

This could include, for example, a nutritionist to help the patient modify his or her diet. “Getting that kind of teaching process in place for a patient might be highly valuable,” he added.

Dr. Duggal disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Basing referral of patients with chronic kidney disease (CKD) to nephrologists on 2-year kidney failure risk exceeding 1% would catch those at higher risk without increasing referral volumes generated from current laboratory-based guidelines, new research indicates.

And combining the two methods – predicted kidney failure risk with lab values – will lead to better patient outcomes by pinpointing CKD patients who most need specialty care, said study author Vishal Duggal, MD, who was a postdoctoral fellow in medical informatics at the Veterans Affairs Palo Alto (Calif.) Health Care System while conducting the research.

“We hope this can provide guidance to primary care physicians and nephrologists to give context for their decision-making,” Dr. Duggal told this news organization.

The VA is the largest provider of CKD care in the United States, developing clinical practice guidelines for CKD management that include suggested indications for nephrology referral based on laboratory values. Laboratory values that are typically used to guide referral include estimated glomerular filtration rate (eGFR) and its rate of decline per year, as well as heavy proteinuria in patients with and without diabetes. 

Dr. Duggal and colleagues – who published their findings in the American Journal of Kidney Diseases – conducted a retrospective analysis of nearly 400,000 veterans with CKD over a yearlong period to determine if referral volume would change if it was based on the estimated risk for kidney failure, rather than solely using laboratory values.

They also estimated the potential volume of nephrology referrals based on a combination of both estimated risk for kidney failure and laboratory data.

Kidney failure risk was calculated using an electronic clinical decision support tool, called Kidney Failure Risk Equation incorporating age, eGFR, gender, and urine albumin-to-creatinine ratio.
 

Targeting fewer patients to specialty care

Among all participants with CKD not already receiving nephrology care, more than 150,000 (41.5%) had a urine albumin or protein measurement leading to computable risk for end-stage kidney disease.

More than 66,200 patients met actual laboratory indications for referral but had not previously seen a nephrologist. Among these patients, 11,752 (17.7%) were referred to nephrology in the following year, and all had a median 2-year predicted risk for kidney failure of 1.5%.

Referred patients were more likely to meet several potential referral criteria, especially eGFR less than 30 mL/min per 1.73 m² and heavy proteinuria. Those with heavy proteinuria with diabetes, or the eGFR indication, had the highest predicted risk for kidney failure at 2 years, at 10% and 7.1% respectively.

Boosting referral volume can be problematic if patients aren’t prioritized by need, Dr. Duggal said, noting that many reasons explain why fewer than one in five CKD patients meeting lab indications for referral aren’t actually referred.

This can include patient preference, he noted: “Kidney disease is a disease of aging, and some patients don’t want to see a specialist or escalate their care.”

“Also, not everyone who has CKD is recommended to see a nephrologist, since primary care physicians do manage a lot of CKD as well.”

Basing referral on predicted kidney failure risk alone, a 2-year risk threshold of at least 1%, would identify a comparable number of patients (n = 72,948) as laboratory-based criteria, the team found, although they note that the patients identified using the KFRE tool would be at higher risk than those identified by lab values alone.

But when they combined the two – a minimum kidney failure risk of at least 1% over 2 years being applied to all new patients meeting lab-based referral indications, those pinpointed for nephrology referral dropped by 42.3%, from 66,276 to an estimated 38,229 patients.

“The current guidelines that just incorporate lab values identify a significant number of patients who are at low risk of developing end-stage kidney disease (ESKD), so incorporating kidney failure risk into current guidelines would target fewer patients to get to specialty care,” Dr. Duggal explained.
 

KFRE tool can be found online

Dr. Duggal emphasized that his findings do not change nephrology referral guidelines, but said physicians can find the KFRE tool online and use it to supplement their decision-making about a patient’s care.

“Further incorporating this [kidney failure] risk into referral practices might highlight a patient at extremely high risk who would benefit more from an interdisciplinary care team,” he said.

This could include, for example, a nutritionist to help the patient modify his or her diet. “Getting that kind of teaching process in place for a patient might be highly valuable,” he added.

Dr. Duggal disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Basing referral of patients with chronic kidney disease (CKD) to nephrologists on 2-year kidney failure risk exceeding 1% would catch those at higher risk without increasing referral volumes generated from current laboratory-based guidelines, new research indicates.

And combining the two methods – predicted kidney failure risk with lab values – will lead to better patient outcomes by pinpointing CKD patients who most need specialty care, said study author Vishal Duggal, MD, who was a postdoctoral fellow in medical informatics at the Veterans Affairs Palo Alto (Calif.) Health Care System while conducting the research.

“We hope this can provide guidance to primary care physicians and nephrologists to give context for their decision-making,” Dr. Duggal told this news organization.

The VA is the largest provider of CKD care in the United States, developing clinical practice guidelines for CKD management that include suggested indications for nephrology referral based on laboratory values. Laboratory values that are typically used to guide referral include estimated glomerular filtration rate (eGFR) and its rate of decline per year, as well as heavy proteinuria in patients with and without diabetes. 

Dr. Duggal and colleagues – who published their findings in the American Journal of Kidney Diseases – conducted a retrospective analysis of nearly 400,000 veterans with CKD over a yearlong period to determine if referral volume would change if it was based on the estimated risk for kidney failure, rather than solely using laboratory values.

They also estimated the potential volume of nephrology referrals based on a combination of both estimated risk for kidney failure and laboratory data.

Kidney failure risk was calculated using an electronic clinical decision support tool, called Kidney Failure Risk Equation incorporating age, eGFR, gender, and urine albumin-to-creatinine ratio.
 

Targeting fewer patients to specialty care

Among all participants with CKD not already receiving nephrology care, more than 150,000 (41.5%) had a urine albumin or protein measurement leading to computable risk for end-stage kidney disease.

More than 66,200 patients met actual laboratory indications for referral but had not previously seen a nephrologist. Among these patients, 11,752 (17.7%) were referred to nephrology in the following year, and all had a median 2-year predicted risk for kidney failure of 1.5%.

Referred patients were more likely to meet several potential referral criteria, especially eGFR less than 30 mL/min per 1.73 m² and heavy proteinuria. Those with heavy proteinuria with diabetes, or the eGFR indication, had the highest predicted risk for kidney failure at 2 years, at 10% and 7.1% respectively.

Boosting referral volume can be problematic if patients aren’t prioritized by need, Dr. Duggal said, noting that many reasons explain why fewer than one in five CKD patients meeting lab indications for referral aren’t actually referred.

This can include patient preference, he noted: “Kidney disease is a disease of aging, and some patients don’t want to see a specialist or escalate their care.”

“Also, not everyone who has CKD is recommended to see a nephrologist, since primary care physicians do manage a lot of CKD as well.”

Basing referral on predicted kidney failure risk alone, a 2-year risk threshold of at least 1%, would identify a comparable number of patients (n = 72,948) as laboratory-based criteria, the team found, although they note that the patients identified using the KFRE tool would be at higher risk than those identified by lab values alone.

But when they combined the two – a minimum kidney failure risk of at least 1% over 2 years being applied to all new patients meeting lab-based referral indications, those pinpointed for nephrology referral dropped by 42.3%, from 66,276 to an estimated 38,229 patients.

“The current guidelines that just incorporate lab values identify a significant number of patients who are at low risk of developing end-stage kidney disease (ESKD), so incorporating kidney failure risk into current guidelines would target fewer patients to get to specialty care,” Dr. Duggal explained.
 

KFRE tool can be found online

Dr. Duggal emphasized that his findings do not change nephrology referral guidelines, but said physicians can find the KFRE tool online and use it to supplement their decision-making about a patient’s care.

“Further incorporating this [kidney failure] risk into referral practices might highlight a patient at extremely high risk who would benefit more from an interdisciplinary care team,” he said.

This could include, for example, a nutritionist to help the patient modify his or her diet. “Getting that kind of teaching process in place for a patient might be highly valuable,” he added.

Dr. Duggal disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved lonapegsomatropin (Skytrofa, Ascendis Pharma), the first weekly subcutaneous injectable growth hormone for children with growth hormone deficiency (GHD).

The approval was based on the findings of the 52-week, phase 3 heiGHt trial in 161 treatment-naive pediatric patients with GHD, which was recently published in the Journal of Clinical Endocrinology & Metabolism.

Since 1987, the standard treatment for pediatric GHD, in which the pituitary gland does not produce enough growth hormone, has been a daily injection of somatropin (recombinant DNA human growth hormone).

“I am excited to be able to reduce the number of shots for some children requiring growth hormone therapy” with this new dosing option, Bradley S. Miller, MD, PhD, who was not involved with the research, said in an email.

“I am hopeful that a once-weekly growth hormone option will improve adherence to growth hormone therapy, leading to improved growth and metabolic outcomes,” added Dr. Miller, professor and division director, pediatric endocrinology, at the University of Minnesota Masonic Children’s Hospital, Minneapolis.

Lonapegsomatropin is approved for the treatment of pediatric patients age 1 year and older who weigh at least 11.5 kg (25.4 pounds) and have short stature due to inadequate secretion of endogenous growth hormone, according to the prescribing information.

The drug molecule consists of a prodrug of somatropin that is inactive when it is bound to a proprietary TransCon (transient conjugation) inert carrier using a TransCon linker. The three-part molecule breaks apart after injection, exposing the active somatropin that is slowly released.

The heiGHt trial demonstrated noninferiority of lonapegsomatropin to somatropin daily injections. Children who received weekly lonapegsomatropin grew 11.2 cm (4.4 inches) per year, whereas those who received an equivalent total dose of somatropin daily injections grew 10.3 cm (4.1 inches) per year.

Safety outcomes – the ratio of bone age to chronologic age, adverse events, tolerability, and immunogenicity – were similar in both groups.
 

Anticipated uptake, other drugs on horizon

Lonapegsomatropin is expected to be available shortly in the United States along with a suite of patient support programs, according to a company press release.

“The impact of the approval of lonapegsomatropin on clinical practice will depend upon its availability, coverage by insurance providers, and patient/provider comfort with using a new product,” Dr. Miller said.

For most pediatric endocrinologists, daily growth hormone has been available their entire careers, so he expects it will take some time for the pediatric endocrinology community to be comfortable prescribing long-acting growth hormone (LAGH), the name given to the once-weekly products.

In the meantime, an FDA decision on another once-weekly growth hormone, somatrogon (OPKO Health/Pfizer) for children with GHD is expected very soon, in October 2021.

And a weekly injectable somapacitan (Sogroya, Novo Nordisk), approved by the FDA in September last year for adults with GHD, is also being studied in children, with estimated study completion in 2024.

“Approval of more LAGH molecules, approval of LAGH for more indications, real-world evidence of safety, efficacy, and improved adherence, and personal experience with LAGH will all likely lead to increased LAGH use over time,” Dr. Miller speculated.

“Over the long-term, I expect insurance providers will cover LAGH products,” he surmised, “but that the price will be similar to or slightly higher than daily growth hormone.”

However, if improved adherence with LAGH is demonstrated and associated with better treatment outcomes, the price of LAGH will likely increase and use of daily growth hormone will decrease, he predicts.

Paul Saenger, MD, who was not involved with the research, believes “all three long-acting growth hormone drugs will eventually be approved for GHD in children.”

“The price will be the same or may be at most 10% more than daily growth hormone replacement,” Dr. Saenger, a pediatric endocrinologist and clinical assistant professor at NYU Long Island School of Medicine, New York, said in an email.

However, daily subcutaneous injections will still be warranted for certain children with GHD, Dr. Miller noted.

“Daily growth hormone may be better than LAGH for a small number of children who have severe GHD associated with hypoglycemia,” he said. “The low levels of growth hormone at the end of the weekly interval of LAGH may allow hypoglycemia to occur in this population.”
 

Phase 3 trial in 161 treatment-naive children with GHD

The heiGHt trial randomized treatment-naive prepubertal children with GHD 2:1 to weekly lonapegsomatropin or daily somatropin (Genotropin, Pfizer) at 73 sites in 15 countries.

The children were a mean age of 8.5 years (range, 3.2-13.1 years), 82% were boys, and 94% were White.

There were no reported serious adverse events or discontinuations related to lonapegsomatropin.

The most common adverse reactions in ≥5% of these pediatric patients were viral infection (15%), pyrexia (15%), cough (11%), nausea and vomiting (11%), hemorrhage (7%), diarrhea (6%), abdominal pain (6%), and arthralgia and arthritis (6%).

Both study groups reported low incidences of transient, non-neutralizing anti-hGH binding antibodies and no cases of persistent antibodies.

Trial limitations include the fact the study was not blinded (as patients received a weekly or daily injection) and drug doses were fixed at 0.24 mg human growth hormone/kg/week, although in real-world clinical practice, doses may be titrated.

Lonapegsomatropin has been studied in more than 300 children with GHD in the phase 3 program in the heiGHt trial (treatment-naive patients), fliGHt trial (treatment-experienced patients), and enliGHten trial (an ongoing long-term extension trial that includes some patients who have been taking lonapegsomatropin for more than 4 years).

The study was sponsored by Ascendis Pharma. Some of the phase 3 study authors are company employees.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved lonapegsomatropin (Skytrofa, Ascendis Pharma), the first weekly subcutaneous injectable growth hormone for children with growth hormone deficiency (GHD).

The approval was based on the findings of the 52-week, phase 3 heiGHt trial in 161 treatment-naive pediatric patients with GHD, which was recently published in the Journal of Clinical Endocrinology & Metabolism.

Since 1987, the standard treatment for pediatric GHD, in which the pituitary gland does not produce enough growth hormone, has been a daily injection of somatropin (recombinant DNA human growth hormone).

“I am excited to be able to reduce the number of shots for some children requiring growth hormone therapy” with this new dosing option, Bradley S. Miller, MD, PhD, who was not involved with the research, said in an email.

“I am hopeful that a once-weekly growth hormone option will improve adherence to growth hormone therapy, leading to improved growth and metabolic outcomes,” added Dr. Miller, professor and division director, pediatric endocrinology, at the University of Minnesota Masonic Children’s Hospital, Minneapolis.

Lonapegsomatropin is approved for the treatment of pediatric patients age 1 year and older who weigh at least 11.5 kg (25.4 pounds) and have short stature due to inadequate secretion of endogenous growth hormone, according to the prescribing information.

The drug molecule consists of a prodrug of somatropin that is inactive when it is bound to a proprietary TransCon (transient conjugation) inert carrier using a TransCon linker. The three-part molecule breaks apart after injection, exposing the active somatropin that is slowly released.

The heiGHt trial demonstrated noninferiority of lonapegsomatropin to somatropin daily injections. Children who received weekly lonapegsomatropin grew 11.2 cm (4.4 inches) per year, whereas those who received an equivalent total dose of somatropin daily injections grew 10.3 cm (4.1 inches) per year.

Safety outcomes – the ratio of bone age to chronologic age, adverse events, tolerability, and immunogenicity – were similar in both groups.
 

Anticipated uptake, other drugs on horizon

Lonapegsomatropin is expected to be available shortly in the United States along with a suite of patient support programs, according to a company press release.

“The impact of the approval of lonapegsomatropin on clinical practice will depend upon its availability, coverage by insurance providers, and patient/provider comfort with using a new product,” Dr. Miller said.

For most pediatric endocrinologists, daily growth hormone has been available their entire careers, so he expects it will take some time for the pediatric endocrinology community to be comfortable prescribing long-acting growth hormone (LAGH), the name given to the once-weekly products.

In the meantime, an FDA decision on another once-weekly growth hormone, somatrogon (OPKO Health/Pfizer) for children with GHD is expected very soon, in October 2021.

And a weekly injectable somapacitan (Sogroya, Novo Nordisk), approved by the FDA in September last year for adults with GHD, is also being studied in children, with estimated study completion in 2024.

“Approval of more LAGH molecules, approval of LAGH for more indications, real-world evidence of safety, efficacy, and improved adherence, and personal experience with LAGH will all likely lead to increased LAGH use over time,” Dr. Miller speculated.

“Over the long-term, I expect insurance providers will cover LAGH products,” he surmised, “but that the price will be similar to or slightly higher than daily growth hormone.”

However, if improved adherence with LAGH is demonstrated and associated with better treatment outcomes, the price of LAGH will likely increase and use of daily growth hormone will decrease, he predicts.

Paul Saenger, MD, who was not involved with the research, believes “all three long-acting growth hormone drugs will eventually be approved for GHD in children.”

“The price will be the same or may be at most 10% more than daily growth hormone replacement,” Dr. Saenger, a pediatric endocrinologist and clinical assistant professor at NYU Long Island School of Medicine, New York, said in an email.

However, daily subcutaneous injections will still be warranted for certain children with GHD, Dr. Miller noted.

“Daily growth hormone may be better than LAGH for a small number of children who have severe GHD associated with hypoglycemia,” he said. “The low levels of growth hormone at the end of the weekly interval of LAGH may allow hypoglycemia to occur in this population.”
 

Phase 3 trial in 161 treatment-naive children with GHD

The heiGHt trial randomized treatment-naive prepubertal children with GHD 2:1 to weekly lonapegsomatropin or daily somatropin (Genotropin, Pfizer) at 73 sites in 15 countries.

The children were a mean age of 8.5 years (range, 3.2-13.1 years), 82% were boys, and 94% were White.

There were no reported serious adverse events or discontinuations related to lonapegsomatropin.

The most common adverse reactions in ≥5% of these pediatric patients were viral infection (15%), pyrexia (15%), cough (11%), nausea and vomiting (11%), hemorrhage (7%), diarrhea (6%), abdominal pain (6%), and arthralgia and arthritis (6%).

Both study groups reported low incidences of transient, non-neutralizing anti-hGH binding antibodies and no cases of persistent antibodies.

Trial limitations include the fact the study was not blinded (as patients received a weekly or daily injection) and drug doses were fixed at 0.24 mg human growth hormone/kg/week, although in real-world clinical practice, doses may be titrated.

Lonapegsomatropin has been studied in more than 300 children with GHD in the phase 3 program in the heiGHt trial (treatment-naive patients), fliGHt trial (treatment-experienced patients), and enliGHten trial (an ongoing long-term extension trial that includes some patients who have been taking lonapegsomatropin for more than 4 years).

The study was sponsored by Ascendis Pharma. Some of the phase 3 study authors are company employees.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved lonapegsomatropin (Skytrofa, Ascendis Pharma), the first weekly subcutaneous injectable growth hormone for children with growth hormone deficiency (GHD).

The approval was based on the findings of the 52-week, phase 3 heiGHt trial in 161 treatment-naive pediatric patients with GHD, which was recently published in the Journal of Clinical Endocrinology & Metabolism.

Since 1987, the standard treatment for pediatric GHD, in which the pituitary gland does not produce enough growth hormone, has been a daily injection of somatropin (recombinant DNA human growth hormone).

“I am excited to be able to reduce the number of shots for some children requiring growth hormone therapy” with this new dosing option, Bradley S. Miller, MD, PhD, who was not involved with the research, said in an email.

“I am hopeful that a once-weekly growth hormone option will improve adherence to growth hormone therapy, leading to improved growth and metabolic outcomes,” added Dr. Miller, professor and division director, pediatric endocrinology, at the University of Minnesota Masonic Children’s Hospital, Minneapolis.

Lonapegsomatropin is approved for the treatment of pediatric patients age 1 year and older who weigh at least 11.5 kg (25.4 pounds) and have short stature due to inadequate secretion of endogenous growth hormone, according to the prescribing information.

The drug molecule consists of a prodrug of somatropin that is inactive when it is bound to a proprietary TransCon (transient conjugation) inert carrier using a TransCon linker. The three-part molecule breaks apart after injection, exposing the active somatropin that is slowly released.

The heiGHt trial demonstrated noninferiority of lonapegsomatropin to somatropin daily injections. Children who received weekly lonapegsomatropin grew 11.2 cm (4.4 inches) per year, whereas those who received an equivalent total dose of somatropin daily injections grew 10.3 cm (4.1 inches) per year.

Safety outcomes – the ratio of bone age to chronologic age, adverse events, tolerability, and immunogenicity – were similar in both groups.
 

Anticipated uptake, other drugs on horizon

Lonapegsomatropin is expected to be available shortly in the United States along with a suite of patient support programs, according to a company press release.

“The impact of the approval of lonapegsomatropin on clinical practice will depend upon its availability, coverage by insurance providers, and patient/provider comfort with using a new product,” Dr. Miller said.

For most pediatric endocrinologists, daily growth hormone has been available their entire careers, so he expects it will take some time for the pediatric endocrinology community to be comfortable prescribing long-acting growth hormone (LAGH), the name given to the once-weekly products.

In the meantime, an FDA decision on another once-weekly growth hormone, somatrogon (OPKO Health/Pfizer) for children with GHD is expected very soon, in October 2021.

And a weekly injectable somapacitan (Sogroya, Novo Nordisk), approved by the FDA in September last year for adults with GHD, is also being studied in children, with estimated study completion in 2024.

“Approval of more LAGH molecules, approval of LAGH for more indications, real-world evidence of safety, efficacy, and improved adherence, and personal experience with LAGH will all likely lead to increased LAGH use over time,” Dr. Miller speculated.

“Over the long-term, I expect insurance providers will cover LAGH products,” he surmised, “but that the price will be similar to or slightly higher than daily growth hormone.”

However, if improved adherence with LAGH is demonstrated and associated with better treatment outcomes, the price of LAGH will likely increase and use of daily growth hormone will decrease, he predicts.

Paul Saenger, MD, who was not involved with the research, believes “all three long-acting growth hormone drugs will eventually be approved for GHD in children.”

“The price will be the same or may be at most 10% more than daily growth hormone replacement,” Dr. Saenger, a pediatric endocrinologist and clinical assistant professor at NYU Long Island School of Medicine, New York, said in an email.

However, daily subcutaneous injections will still be warranted for certain children with GHD, Dr. Miller noted.

“Daily growth hormone may be better than LAGH for a small number of children who have severe GHD associated with hypoglycemia,” he said. “The low levels of growth hormone at the end of the weekly interval of LAGH may allow hypoglycemia to occur in this population.”
 

Phase 3 trial in 161 treatment-naive children with GHD

The heiGHt trial randomized treatment-naive prepubertal children with GHD 2:1 to weekly lonapegsomatropin or daily somatropin (Genotropin, Pfizer) at 73 sites in 15 countries.

The children were a mean age of 8.5 years (range, 3.2-13.1 years), 82% were boys, and 94% were White.

There were no reported serious adverse events or discontinuations related to lonapegsomatropin.

The most common adverse reactions in ≥5% of these pediatric patients were viral infection (15%), pyrexia (15%), cough (11%), nausea and vomiting (11%), hemorrhage (7%), diarrhea (6%), abdominal pain (6%), and arthralgia and arthritis (6%).

Both study groups reported low incidences of transient, non-neutralizing anti-hGH binding antibodies and no cases of persistent antibodies.

Trial limitations include the fact the study was not blinded (as patients received a weekly or daily injection) and drug doses were fixed at 0.24 mg human growth hormone/kg/week, although in real-world clinical practice, doses may be titrated.

Lonapegsomatropin has been studied in more than 300 children with GHD in the phase 3 program in the heiGHt trial (treatment-naive patients), fliGHt trial (treatment-experienced patients), and enliGHten trial (an ongoing long-term extension trial that includes some patients who have been taking lonapegsomatropin for more than 4 years).

The study was sponsored by Ascendis Pharma. Some of the phase 3 study authors are company employees.

A version of this article first appeared on Medscape.com.

The featured report from the 6,000-patient EMPEROR-Preserved trial at the virtual annual congress of the European Society of Cardiology drew lots of attention for its headline finding: the first unequivocal demonstration that a medication, empagliflozin, can significantly reduce the rate of cardiovascular death and hospitalization for heart failure in patients with heart failure with preserved ejection fraction (HFpEF, a left ventricular ejection fraction of more than 40%), with the details simultaneously published online.

But at the same time, the EMPEROR-Preserved investigators released four additional reports with a lot more outcome analyses that also deserve some attention.
 

The puzzling neutral effect on renal events

Perhaps the most surprising and complicated set of findings among the main EMPEROR-Preserved outcomes involved renal outcomes.

The trial’s primary outcome was the combined rate of cardiovascular death or hospitalization for heart failure (HHF), and the results showed that treatment with empagliflozin (Jardiance) for a median of 26 months on top of standard treatment for patients with HFpEF led to a significant 21% relative risk reduction, compared with placebo-treated patients.

The trial had two prespecified secondary outcomes. One was the total number of HHF, which dropped by a significant 27%, compared with placebo. The second was the mean change in slope of estimated glomerular filtration rate (eGFR) on an annualized basis, and the empagliflozin regimen reduced the cumulative annual deficit, compared with placebo by an average of 1.36 mL/min per 1.73 m^2, a significant difference.

This preservation of renal function was consistent with results from many prior studies of empagliflozin and all of the other U.S.-approved agents from the sodium-glucose cotransporter 2 inhibitor class. Preservation of renal function and a reduction in renal events has become a hallmark property of all agents in the SGLT2 inhibitor class both in patients with type 2 diabetes, as well as in those without diabetes but with heart failure with reduced ejection fraction (HFrEF) or with chronic kidney disease.

EMPEROR-Preserved threw a wrench into what had been an unbroken history of renal protection by SGLT2 inhibitors. That happened when a prespecified endpoint of the study – a composite renal outcome defined as time to first occurrence of chronic dialysis, renal transplantation, a sustained reduction of at least 40% in eGFR, or a sustained drop in eGFR of more than 10 or 15 mL/min per 1.73 m2 from baseline – yielded an unexpected neutral finding.

For this composite renal outcome, EMPEROR-Preserved showed a nonsignificant 5% reduction, compared with placebo, a result that both differed from what had been seen in essentially all the other SGLT2 inhibitor trials that had looked at this, but which also seemed at odds with the observed significant preservation of renal function that seemed substantial enough to produce a clinically meaningful benefit.
 

Renal effects blunted in HFpEF

The immediate upshot was a letter published by several EMPEROR-Preserved investigators that spelled out this discrepancy and came to the jolting conclusion that “eGFR slope analysis has limitations as a surrogate for predicting the effect of drugs on renal outcomes in patients with heart failure.”

The same authors, along with some additional associates, also published a second letter that noted a further unexpected twist with the renal outcome: “In prior large-scale clinical trials, the effect of SGLT2 inhibitors on heart failure and renal outcomes had consistently tracked together,” they noted, but in this case it didn’t, a discordance they said was “extraordinarily puzzling”.

MDedge News

This led the study’s leaders to reanalyze the renal outcomes using a different definition, one that Milton Packer, MD, who helped design the trial and oversaw several of its analyses, called “a more conventional definition of renal events,” during his presentation of these findings at the congress. The researchers swapped out a 40% drop from baseline eGFR as an event and replaced it with a 50% decline, a change designed to screen out less severe, and often transient, reductions in kidney function that have less lasting impact on health. They also added an additional component to the composite endpoint, renal death. A revised analysis using this new renal composite outcome appeared in the European Journal of Heart Failure letter.

This change cut the total number of renal events tallied in the trial nearly in half, down to 112, and showed a more robust decline in renal events with empagliflozin treatment compared with the initial analysis, although the drop remained nonsignificant. The revised analysis also showed that the overall, nonsignificant 22% relative reduction in renal events in patients on empagliflozin, compared with placebo, dwindled down to completely nonexistent in the tertile of patients with a left ventricular ejection fraction of 60% or greater. In this tertile the hazard ratio actually showed a nonsignificant point estimate of a 24% increased rate of renal events on empagliflozin, with the caveat that this subgroup now included a total of just 40 total events between the two treatment arms. (Each of the two other tertiles also had roughly the same number of total events.)

The biggest effect on renal-event reduction was in the tertile of patients with an ejection fraction of 41%-49%, in which empagliflozin treatment was linked with a significant 59% cut in renal events, compared with placebo. The analysis also showed significant heterogeneity in thus outcome between this subgroup and the other two tertiles that had higher ejection fractions and showed reduced rates of protection by empagliflozin against renal events.

This apparent blunting of a renal effect despite preservation of renal function seemed to mimic the blunting of the primary cardiovascular outcome effect that also appeared in patients with ejection fractions in the 60%-65% range or above.

“If we knew what blunted the effect of empagliflozin on heart failure outcomes at higher ejection fraction levels, we think the same explanation may also apply to the blunting of effect on renal outcomes, but right now we do not know the answer to either question,” Dr. Packer said in an interview. He’s suggested that one possibility is that many of the enrolled patients identified as having HFpEF, but with these high ejection fractions may have not actually had HFpEF, and their signs and symptoms may have instead resulted from atrial fibrillation.

“Many patients with an ejection fraction of 60%-65% and above had atrial fibrillation,” he noted, with a prevalence at enrollment in this subgroup of about 50%. Atrial fibrillation can cause dyspnea, a hallmark symptom leading to diagnosis of heart failure, and it also increases levels of N-terminal of the prohormone brain natriuretic peptide, a metric that served as a gatekeeper for entry into the trial. “Essentially, we are saying that many of the criteria that we specified to ensure that patients had heart failure probably did not work very well in patients with an ejection fraction of 65% or greater,” said Dr. Packer, a cardiologist at Baylor University Medical Center in Dallas. “We need to figure out who these patients are.”

Some experts not involved with the study voiced skepticism that the renal findings reflected a real issue.

“I’m quite optimistic that in the long-term the effect on eGFR will translate into renal protection,” said Rudolf A. de Boer, MD, PhD, a professor of translational cardiology at University Medical Center Groningen (the Netherlands), and designated discussant at the congress for the presentation by Dr. Packer.

Catherine Hackett/MDedge News

John J.V. McMurray, MD, a professor of cardiology and a heart failure specialist at Glasgow University, speculated that the unexpected renal outcomes data may relate to the initial decline in renal function produced by treatment with SGLT2 inhibitors despite their longer-term enhancement of renal protection.

“If you use a treatment that protects the kidneys in the long-term but causes an initial dip in eGFR, more patients receiving that treatment will have an early ‘event,’ ” he noted in an interview. He also cautioned about the dangers of subgroup analyses that dice the study population into small cohorts.

“Trials are powered to look at the effect of treatment in the overall population. Everything else is exploratory, underpowered, and subject to the play of chance,” Dr. McMurray stressed.
 

Counting additional cardiovascular disease events allows more analyses

A third auxiliary report from the EMPEROR-Preserved investigators performed several prespecified analyses that depended on adding additional cardiovascular disease endpoints to the core tallies of cardiovascular death or HHF – such as emergent, urgent, and outpatient events that reflected worsening heart failure – and also included information on diuretic and vasopressor use because of worsening heart failure. The increased event numbers allowed the researchers to perform 30 additional analyses included in this report, according to the count kept by Dr. Packer who was the lead author.

He highlighted several of the additional results in this paper that documented benefits from empagliflozin treatment, compared with placebo:

• A significant 29% reduction in the need for admission to a cardiac care unit or intensive care unit during an HHF.
• A nonsignificant 33% reduction in the need for intravenous vasopressors or positive inotropic drugs during HHF.
• A significantly increased rate of patients achieving a higher New York Heart Association functional class. For example, after the first year of treatment patients who received empagliflozin had a 37% higher rate of functional class improvement, compared with patients who received placebo.

Dr. McMurray had his own list of key takeaways from this paper, including:

• Among patients who needed hospitalization, “those treated with empagliflozin were less sick than those in the placebo group.”
• In addition to reducing HHF empagliflozin treatment also reduced episodes of outpatient worsening as reflected by their receipt of intensified diuretic treatment, which occurred a significant 27% less often, compared with patients on placebo.
• Treatment with empagliflozin also linked with a significant 39% relative reduction in emergency or urgent-care visits that required intravenous therapy.

Empagliflozin’s performance relative to sacubitril/valsartan

The fourth additional report focused on a post hoc, cross-trial comparison of the results from EMPEROR-Preserved and from another recent trial that, like EMPEROR-Preserved, assessed in patients with HFpEF a drug previously proven to work quite well in patients with HFrEF. The comparator drug was sacubitril/valsartan (Entresto), which underwent testing in patients with HFpEF in the PARAGON-HF trial.

The primary outcome of PARAGON-HF, which randomized 4,822 patients, was reduction in cardiovascular death and in total HHF. This dropped by a relative 13%, compared with placebo, during a median of 35 months, a between-group difference that came close to but did not achieve significance (P = .06). Despite this limitation, the Food and Drug Administration in February 2021 loosened the indication for using sacubitril/valsartan in patients with heart failure and a “below normal” ejection fraction, a category that can include many patients considered to have HFpEF.

Although the researchers who ran this analysis, including Dr. Packer, who was the first author, admitted that “comparison of effect sizes across trials is fraught with difficulties,” they nonetheless concluded from their analysis that “for all outcomes that included HHF the effect size was larger for empagliflozin than for sacubitril/valsartan.”

Dr. McMurray, a lead instigator for PARAGON-HF, said there was little to take away from this analysis.

“The patient populations were different, and sacubitril/valsartan was compared against an active therapy, valsartan,” while in EMPEROR-Preserved empagliflozin compared against placebo. “Most of us believe that sacubitril/valsartan and SGLT2 inhibitors work in different but complementary ways, and their benefits are additive. You would want patients with HFpEF or HFrEF to take both,” he said in an interview.

Dr. Packer agreed with that approach and added that he would probably also prescribe a third agent, spironolactone, to many patients with HFpEF.

EMPEROR-Preserved was sponsored by Boehringer Ingelheim and Eli Lilly, which jointly market empagliflozin (Jardiance). PARAGON-HF was sponsored by Novartis, which markets sacubitril/valsartan (Entresto). Dr. Packer has received consulting fees from Boehringer Ingelheim and from numerous other companies. Dr. de Boer has research contracts with Boehringer Ingelheim as well as from Abbott, AstraZeneca, Cardior, Ionis, Novo Nordisk, and Roche, and he has been a consultant to Novartis as well as to Abbott, AstraZeneca, Gayer, and Roche. Dr. McMurray led trials of sacubitril/valsartan sponsored by Novartis, and his institution has received compensation for his participation in studies sponsored by Abbvie, AstraZeneca, Cardurion, DalCor, GlaxoSmithKline, Pfizer, and Theracos.

[email protected]

The featured report from the 6,000-patient EMPEROR-Preserved trial at the virtual annual congress of the European Society of Cardiology drew lots of attention for its headline finding: the first unequivocal demonstration that a medication, empagliflozin, can significantly reduce the rate of cardiovascular death and hospitalization for heart failure in patients with heart failure with preserved ejection fraction (HFpEF, a left ventricular ejection fraction of more than 40%), with the details simultaneously published online.

But at the same time, the EMPEROR-Preserved investigators released four additional reports with a lot more outcome analyses that also deserve some attention.
 

The puzzling neutral effect on renal events

Perhaps the most surprising and complicated set of findings among the main EMPEROR-Preserved outcomes involved renal outcomes.

The trial’s primary outcome was the combined rate of cardiovascular death or hospitalization for heart failure (HHF), and the results showed that treatment with empagliflozin (Jardiance) for a median of 26 months on top of standard treatment for patients with HFpEF led to a significant 21% relative risk reduction, compared with placebo-treated patients.

The trial had two prespecified secondary outcomes. One was the total number of HHF, which dropped by a significant 27%, compared with placebo. The second was the mean change in slope of estimated glomerular filtration rate (eGFR) on an annualized basis, and the empagliflozin regimen reduced the cumulative annual deficit, compared with placebo by an average of 1.36 mL/min per 1.73 m^2, a significant difference.

This preservation of renal function was consistent with results from many prior studies of empagliflozin and all of the other U.S.-approved agents from the sodium-glucose cotransporter 2 inhibitor class. Preservation of renal function and a reduction in renal events has become a hallmark property of all agents in the SGLT2 inhibitor class both in patients with type 2 diabetes, as well as in those without diabetes but with heart failure with reduced ejection fraction (HFrEF) or with chronic kidney disease.

EMPEROR-Preserved threw a wrench into what had been an unbroken history of renal protection by SGLT2 inhibitors. That happened when a prespecified endpoint of the study – a composite renal outcome defined as time to first occurrence of chronic dialysis, renal transplantation, a sustained reduction of at least 40% in eGFR, or a sustained drop in eGFR of more than 10 or 15 mL/min per 1.73 m2 from baseline – yielded an unexpected neutral finding.

For this composite renal outcome, EMPEROR-Preserved showed a nonsignificant 5% reduction, compared with placebo, a result that both differed from what had been seen in essentially all the other SGLT2 inhibitor trials that had looked at this, but which also seemed at odds with the observed significant preservation of renal function that seemed substantial enough to produce a clinically meaningful benefit.
 

Renal effects blunted in HFpEF

The immediate upshot was a letter published by several EMPEROR-Preserved investigators that spelled out this discrepancy and came to the jolting conclusion that “eGFR slope analysis has limitations as a surrogate for predicting the effect of drugs on renal outcomes in patients with heart failure.”

The same authors, along with some additional associates, also published a second letter that noted a further unexpected twist with the renal outcome: “In prior large-scale clinical trials, the effect of SGLT2 inhibitors on heart failure and renal outcomes had consistently tracked together,” they noted, but in this case it didn’t, a discordance they said was “extraordinarily puzzling”.

MDedge News

This led the study’s leaders to reanalyze the renal outcomes using a different definition, one that Milton Packer, MD, who helped design the trial and oversaw several of its analyses, called “a more conventional definition of renal events,” during his presentation of these findings at the congress. The researchers swapped out a 40% drop from baseline eGFR as an event and replaced it with a 50% decline, a change designed to screen out less severe, and often transient, reductions in kidney function that have less lasting impact on health. They also added an additional component to the composite endpoint, renal death. A revised analysis using this new renal composite outcome appeared in the European Journal of Heart Failure letter.

This change cut the total number of renal events tallied in the trial nearly in half, down to 112, and showed a more robust decline in renal events with empagliflozin treatment compared with the initial analysis, although the drop remained nonsignificant. The revised analysis also showed that the overall, nonsignificant 22% relative reduction in renal events in patients on empagliflozin, compared with placebo, dwindled down to completely nonexistent in the tertile of patients with a left ventricular ejection fraction of 60% or greater. In this tertile the hazard ratio actually showed a nonsignificant point estimate of a 24% increased rate of renal events on empagliflozin, with the caveat that this subgroup now included a total of just 40 total events between the two treatment arms. (Each of the two other tertiles also had roughly the same number of total events.)

The biggest effect on renal-event reduction was in the tertile of patients with an ejection fraction of 41%-49%, in which empagliflozin treatment was linked with a significant 59% cut in renal events, compared with placebo. The analysis also showed significant heterogeneity in thus outcome between this subgroup and the other two tertiles that had higher ejection fractions and showed reduced rates of protection by empagliflozin against renal events.

This apparent blunting of a renal effect despite preservation of renal function seemed to mimic the blunting of the primary cardiovascular outcome effect that also appeared in patients with ejection fractions in the 60%-65% range or above.

“If we knew what blunted the effect of empagliflozin on heart failure outcomes at higher ejection fraction levels, we think the same explanation may also apply to the blunting of effect on renal outcomes, but right now we do not know the answer to either question,” Dr. Packer said in an interview. He’s suggested that one possibility is that many of the enrolled patients identified as having HFpEF, but with these high ejection fractions may have not actually had HFpEF, and their signs and symptoms may have instead resulted from atrial fibrillation.

“Many patients with an ejection fraction of 60%-65% and above had atrial fibrillation,” he noted, with a prevalence at enrollment in this subgroup of about 50%. Atrial fibrillation can cause dyspnea, a hallmark symptom leading to diagnosis of heart failure, and it also increases levels of N-terminal of the prohormone brain natriuretic peptide, a metric that served as a gatekeeper for entry into the trial. “Essentially, we are saying that many of the criteria that we specified to ensure that patients had heart failure probably did not work very well in patients with an ejection fraction of 65% or greater,” said Dr. Packer, a cardiologist at Baylor University Medical Center in Dallas. “We need to figure out who these patients are.”

Some experts not involved with the study voiced skepticism that the renal findings reflected a real issue.

“I’m quite optimistic that in the long-term the effect on eGFR will translate into renal protection,” said Rudolf A. de Boer, MD, PhD, a professor of translational cardiology at University Medical Center Groningen (the Netherlands), and designated discussant at the congress for the presentation by Dr. Packer.

Catherine Hackett/MDedge News

John J.V. McMurray, MD, a professor of cardiology and a heart failure specialist at Glasgow University, speculated that the unexpected renal outcomes data may relate to the initial decline in renal function produced by treatment with SGLT2 inhibitors despite their longer-term enhancement of renal protection.

“If you use a treatment that protects the kidneys in the long-term but causes an initial dip in eGFR, more patients receiving that treatment will have an early ‘event,’ ” he noted in an interview. He also cautioned about the dangers of subgroup analyses that dice the study population into small cohorts.

“Trials are powered to look at the effect of treatment in the overall population. Everything else is exploratory, underpowered, and subject to the play of chance,” Dr. McMurray stressed.
 

Counting additional cardiovascular disease events allows more analyses

A third auxiliary report from the EMPEROR-Preserved investigators performed several prespecified analyses that depended on adding additional cardiovascular disease endpoints to the core tallies of cardiovascular death or HHF – such as emergent, urgent, and outpatient events that reflected worsening heart failure – and also included information on diuretic and vasopressor use because of worsening heart failure. The increased event numbers allowed the researchers to perform 30 additional analyses included in this report, according to the count kept by Dr. Packer who was the lead author.

He highlighted several of the additional results in this paper that documented benefits from empagliflozin treatment, compared with placebo:

• A significant 29% reduction in the need for admission to a cardiac care unit or intensive care unit during an HHF.
• A nonsignificant 33% reduction in the need for intravenous vasopressors or positive inotropic drugs during HHF.
• A significantly increased rate of patients achieving a higher New York Heart Association functional class. For example, after the first year of treatment patients who received empagliflozin had a 37% higher rate of functional class improvement, compared with patients who received placebo.

Dr. McMurray had his own list of key takeaways from this paper, including:

• Among patients who needed hospitalization, “those treated with empagliflozin were less sick than those in the placebo group.”
• In addition to reducing HHF empagliflozin treatment also reduced episodes of outpatient worsening as reflected by their receipt of intensified diuretic treatment, which occurred a significant 27% less often, compared with patients on placebo.
• Treatment with empagliflozin also linked with a significant 39% relative reduction in emergency or urgent-care visits that required intravenous therapy.

Empagliflozin’s performance relative to sacubitril/valsartan

The fourth additional report focused on a post hoc, cross-trial comparison of the results from EMPEROR-Preserved and from another recent trial that, like EMPEROR-Preserved, assessed in patients with HFpEF a drug previously proven to work quite well in patients with HFrEF. The comparator drug was sacubitril/valsartan (Entresto), which underwent testing in patients with HFpEF in the PARAGON-HF trial.

The primary outcome of PARAGON-HF, which randomized 4,822 patients, was reduction in cardiovascular death and in total HHF. This dropped by a relative 13%, compared with placebo, during a median of 35 months, a between-group difference that came close to but did not achieve significance (P = .06). Despite this limitation, the Food and Drug Administration in February 2021 loosened the indication for using sacubitril/valsartan in patients with heart failure and a “below normal” ejection fraction, a category that can include many patients considered to have HFpEF.

Although the researchers who ran this analysis, including Dr. Packer, who was the first author, admitted that “comparison of effect sizes across trials is fraught with difficulties,” they nonetheless concluded from their analysis that “for all outcomes that included HHF the effect size was larger for empagliflozin than for sacubitril/valsartan.”

Dr. McMurray, a lead instigator for PARAGON-HF, said there was little to take away from this analysis.

“The patient populations were different, and sacubitril/valsartan was compared against an active therapy, valsartan,” while in EMPEROR-Preserved empagliflozin compared against placebo. “Most of us believe that sacubitril/valsartan and SGLT2 inhibitors work in different but complementary ways, and their benefits are additive. You would want patients with HFpEF or HFrEF to take both,” he said in an interview.

Dr. Packer agreed with that approach and added that he would probably also prescribe a third agent, spironolactone, to many patients with HFpEF.

EMPEROR-Preserved was sponsored by Boehringer Ingelheim and Eli Lilly, which jointly market empagliflozin (Jardiance). PARAGON-HF was sponsored by Novartis, which markets sacubitril/valsartan (Entresto). Dr. Packer has received consulting fees from Boehringer Ingelheim and from numerous other companies. Dr. de Boer has research contracts with Boehringer Ingelheim as well as from Abbott, AstraZeneca, Cardior, Ionis, Novo Nordisk, and Roche, and he has been a consultant to Novartis as well as to Abbott, AstraZeneca, Gayer, and Roche. Dr. McMurray led trials of sacubitril/valsartan sponsored by Novartis, and his institution has received compensation for his participation in studies sponsored by Abbvie, AstraZeneca, Cardurion, DalCor, GlaxoSmithKline, Pfizer, and Theracos.

[email protected]

The featured report from the 6,000-patient EMPEROR-Preserved trial at the virtual annual congress of the European Society of Cardiology drew lots of attention for its headline finding: the first unequivocal demonstration that a medication, empagliflozin, can significantly reduce the rate of cardiovascular death and hospitalization for heart failure in patients with heart failure with preserved ejection fraction (HFpEF, a left ventricular ejection fraction of more than 40%), with the details simultaneously published online.

But at the same time, the EMPEROR-Preserved investigators released four additional reports with a lot more outcome analyses that also deserve some attention.
 

The puzzling neutral effect on renal events

Perhaps the most surprising and complicated set of findings among the main EMPEROR-Preserved outcomes involved renal outcomes.

The trial’s primary outcome was the combined rate of cardiovascular death or hospitalization for heart failure (HHF), and the results showed that treatment with empagliflozin (Jardiance) for a median of 26 months on top of standard treatment for patients with HFpEF led to a significant 21% relative risk reduction, compared with placebo-treated patients.

The trial had two prespecified secondary outcomes. One was the total number of HHF, which dropped by a significant 27%, compared with placebo. The second was the mean change in slope of estimated glomerular filtration rate (eGFR) on an annualized basis, and the empagliflozin regimen reduced the cumulative annual deficit, compared with placebo by an average of 1.36 mL/min per 1.73 m^2, a significant difference.

This preservation of renal function was consistent with results from many prior studies of empagliflozin and all of the other U.S.-approved agents from the sodium-glucose cotransporter 2 inhibitor class. Preservation of renal function and a reduction in renal events has become a hallmark property of all agents in the SGLT2 inhibitor class both in patients with type 2 diabetes, as well as in those without diabetes but with heart failure with reduced ejection fraction (HFrEF) or with chronic kidney disease.

EMPEROR-Preserved threw a wrench into what had been an unbroken history of renal protection by SGLT2 inhibitors. That happened when a prespecified endpoint of the study – a composite renal outcome defined as time to first occurrence of chronic dialysis, renal transplantation, a sustained reduction of at least 40% in eGFR, or a sustained drop in eGFR of more than 10 or 15 mL/min per 1.73 m2 from baseline – yielded an unexpected neutral finding.

For this composite renal outcome, EMPEROR-Preserved showed a nonsignificant 5% reduction, compared with placebo, a result that both differed from what had been seen in essentially all the other SGLT2 inhibitor trials that had looked at this, but which also seemed at odds with the observed significant preservation of renal function that seemed substantial enough to produce a clinically meaningful benefit.
 

Renal effects blunted in HFpEF

The immediate upshot was a letter published by several EMPEROR-Preserved investigators that spelled out this discrepancy and came to the jolting conclusion that “eGFR slope analysis has limitations as a surrogate for predicting the effect of drugs on renal outcomes in patients with heart failure.”

The same authors, along with some additional associates, also published a second letter that noted a further unexpected twist with the renal outcome: “In prior large-scale clinical trials, the effect of SGLT2 inhibitors on heart failure and renal outcomes had consistently tracked together,” they noted, but in this case it didn’t, a discordance they said was “extraordinarily puzzling”.

MDedge News

This led the study’s leaders to reanalyze the renal outcomes using a different definition, one that Milton Packer, MD, who helped design the trial and oversaw several of its analyses, called “a more conventional definition of renal events,” during his presentation of these findings at the congress. The researchers swapped out a 40% drop from baseline eGFR as an event and replaced it with a 50% decline, a change designed to screen out less severe, and often transient, reductions in kidney function that have less lasting impact on health. They also added an additional component to the composite endpoint, renal death. A revised analysis using this new renal composite outcome appeared in the European Journal of Heart Failure letter.

This change cut the total number of renal events tallied in the trial nearly in half, down to 112, and showed a more robust decline in renal events with empagliflozin treatment compared with the initial analysis, although the drop remained nonsignificant. The revised analysis also showed that the overall, nonsignificant 22% relative reduction in renal events in patients on empagliflozin, compared with placebo, dwindled down to completely nonexistent in the tertile of patients with a left ventricular ejection fraction of 60% or greater. In this tertile the hazard ratio actually showed a nonsignificant point estimate of a 24% increased rate of renal events on empagliflozin, with the caveat that this subgroup now included a total of just 40 total events between the two treatment arms. (Each of the two other tertiles also had roughly the same number of total events.)

The biggest effect on renal-event reduction was in the tertile of patients with an ejection fraction of 41%-49%, in which empagliflozin treatment was linked with a significant 59% cut in renal events, compared with placebo. The analysis also showed significant heterogeneity in thus outcome between this subgroup and the other two tertiles that had higher ejection fractions and showed reduced rates of protection by empagliflozin against renal events.

This apparent blunting of a renal effect despite preservation of renal function seemed to mimic the blunting of the primary cardiovascular outcome effect that also appeared in patients with ejection fractions in the 60%-65% range or above.

“If we knew what blunted the effect of empagliflozin on heart failure outcomes at higher ejection fraction levels, we think the same explanation may also apply to the blunting of effect on renal outcomes, but right now we do not know the answer to either question,” Dr. Packer said in an interview. He’s suggested that one possibility is that many of the enrolled patients identified as having HFpEF, but with these high ejection fractions may have not actually had HFpEF, and their signs and symptoms may have instead resulted from atrial fibrillation.

“Many patients with an ejection fraction of 60%-65% and above had atrial fibrillation,” he noted, with a prevalence at enrollment in this subgroup of about 50%. Atrial fibrillation can cause dyspnea, a hallmark symptom leading to diagnosis of heart failure, and it also increases levels of N-terminal of the prohormone brain natriuretic peptide, a metric that served as a gatekeeper for entry into the trial. “Essentially, we are saying that many of the criteria that we specified to ensure that patients had heart failure probably did not work very well in patients with an ejection fraction of 65% or greater,” said Dr. Packer, a cardiologist at Baylor University Medical Center in Dallas. “We need to figure out who these patients are.”

Some experts not involved with the study voiced skepticism that the renal findings reflected a real issue.

“I’m quite optimistic that in the long-term the effect on eGFR will translate into renal protection,” said Rudolf A. de Boer, MD, PhD, a professor of translational cardiology at University Medical Center Groningen (the Netherlands), and designated discussant at the congress for the presentation by Dr. Packer.

Catherine Hackett/MDedge News

John J.V. McMurray, MD, a professor of cardiology and a heart failure specialist at Glasgow University, speculated that the unexpected renal outcomes data may relate to the initial decline in renal function produced by treatment with SGLT2 inhibitors despite their longer-term enhancement of renal protection.

“If you use a treatment that protects the kidneys in the long-term but causes an initial dip in eGFR, more patients receiving that treatment will have an early ‘event,’ ” he noted in an interview. He also cautioned about the dangers of subgroup analyses that dice the study population into small cohorts.

“Trials are powered to look at the effect of treatment in the overall population. Everything else is exploratory, underpowered, and subject to the play of chance,” Dr. McMurray stressed.
 

Counting additional cardiovascular disease events allows more analyses

A third auxiliary report from the EMPEROR-Preserved investigators performed several prespecified analyses that depended on adding additional cardiovascular disease endpoints to the core tallies of cardiovascular death or HHF – such as emergent, urgent, and outpatient events that reflected worsening heart failure – and also included information on diuretic and vasopressor use because of worsening heart failure. The increased event numbers allowed the researchers to perform 30 additional analyses included in this report, according to the count kept by Dr. Packer who was the lead author.

He highlighted several of the additional results in this paper that documented benefits from empagliflozin treatment, compared with placebo:

• A significant 29% reduction in the need for admission to a cardiac care unit or intensive care unit during an HHF.
• A nonsignificant 33% reduction in the need for intravenous vasopressors or positive inotropic drugs during HHF.
• A significantly increased rate of patients achieving a higher New York Heart Association functional class. For example, after the first year of treatment patients who received empagliflozin had a 37% higher rate of functional class improvement, compared with patients who received placebo.

Dr. McMurray had his own list of key takeaways from this paper, including:

• Among patients who needed hospitalization, “those treated with empagliflozin were less sick than those in the placebo group.”
• In addition to reducing HHF empagliflozin treatment also reduced episodes of outpatient worsening as reflected by their receipt of intensified diuretic treatment, which occurred a significant 27% less often, compared with patients on placebo.
• Treatment with empagliflozin also linked with a significant 39% relative reduction in emergency or urgent-care visits that required intravenous therapy.

Empagliflozin’s performance relative to sacubitril/valsartan

The fourth additional report focused on a post hoc, cross-trial comparison of the results from EMPEROR-Preserved and from another recent trial that, like EMPEROR-Preserved, assessed in patients with HFpEF a drug previously proven to work quite well in patients with HFrEF. The comparator drug was sacubitril/valsartan (Entresto), which underwent testing in patients with HFpEF in the PARAGON-HF trial.

The primary outcome of PARAGON-HF, which randomized 4,822 patients, was reduction in cardiovascular death and in total HHF. This dropped by a relative 13%, compared with placebo, during a median of 35 months, a between-group difference that came close to but did not achieve significance (P = .06). Despite this limitation, the Food and Drug Administration in February 2021 loosened the indication for using sacubitril/valsartan in patients with heart failure and a “below normal” ejection fraction, a category that can include many patients considered to have HFpEF.

Although the researchers who ran this analysis, including Dr. Packer, who was the first author, admitted that “comparison of effect sizes across trials is fraught with difficulties,” they nonetheless concluded from their analysis that “for all outcomes that included HHF the effect size was larger for empagliflozin than for sacubitril/valsartan.”

Dr. McMurray, a lead instigator for PARAGON-HF, said there was little to take away from this analysis.

“The patient populations were different, and sacubitril/valsartan was compared against an active therapy, valsartan,” while in EMPEROR-Preserved empagliflozin compared against placebo. “Most of us believe that sacubitril/valsartan and SGLT2 inhibitors work in different but complementary ways, and their benefits are additive. You would want patients with HFpEF or HFrEF to take both,” he said in an interview.

Dr. Packer agreed with that approach and added that he would probably also prescribe a third agent, spironolactone, to many patients with HFpEF.

EMPEROR-Preserved was sponsored by Boehringer Ingelheim and Eli Lilly, which jointly market empagliflozin (Jardiance). PARAGON-HF was sponsored by Novartis, which markets sacubitril/valsartan (Entresto). Dr. Packer has received consulting fees from Boehringer Ingelheim and from numerous other companies. Dr. de Boer has research contracts with Boehringer Ingelheim as well as from Abbott, AstraZeneca, Cardior, Ionis, Novo Nordisk, and Roche, and he has been a consultant to Novartis as well as to Abbott, AstraZeneca, Gayer, and Roche. Dr. McMurray led trials of sacubitril/valsartan sponsored by Novartis, and his institution has received compensation for his participation in studies sponsored by Abbvie, AstraZeneca, Cardurion, DalCor, GlaxoSmithKline, Pfizer, and Theracos.

[email protected]

Healthy elderly people who ate a walnut-supplemented diet for 2 years showed significant reductions in LDL cholesterol, according to a randomized study that used imaging to evaluate lipid changes.

©rootstocks/Thinkstock

“Regularly eating walnuts will lower your LDL cholesterol and improve the quality of LDL particles, rendering them less prone to enter the arterial wall and build up atherosclerosis, and this will occur without unwanted weight gain in spite of the high-fat – healthy vegetable fat, though – content of walnuts,” Emilio Ros, MD, PhD, senior author of the Walnuts and Healthy Aging (WAHA) study, said in an interview.

WAHA is a parallel-group, randomized, controlled trial that followed 636 patients over 2 years at centers in Loma Linda, Calif., and Barcelona. They were randomly assigned to either a walnut-free or walnut-supplemented diet, and every 2 months they were underwent nuclear magnetic resonance spectroscopy and recorded their compliance, toleration, medication changes, and body weight.

The researchers reported “significantly decreased” total cholesterol, LDL cholesterol and intermediate-density lipoprotein cholesterol, along with reductions in total LDL cholesterol particles and small LDL cholesterol particle number in patients on a walnut-supplemented diet, compared with controls. However, triglycerides and HDL cholesterol were unaffected.

Study results

The study reported mean reductions in the following lipid categories among what the researchers called the “walnut group”:

• Total cholesterol, –8.5 mg/dL (95% confidence interval, –11.2 to –5.4), a 4.4% mean reduction.
• LDL-C, –4.3 mg/dL (95% CI, –6.6 to –1.6), a 3.6% reduction.
• Intermediate-density lipoprotein cholesterol, –1.3 mg/dL (95% CI, –1.5 to –1.0] for a 16.8% reduction.
• Total LDL cholesterol particles, a reduction of 4.3%.
• Small LDL cholesterol particle number, a 6.1% decrease.

“WAHA is the largest and longest randomized nut trial to date, which overcomes power limitations of former trials, smaller and of shorter duration,” said Dr. Ros, of the lipid clinic, endocrinology, nutrition service at the Hospital Clinic Villarroel at the University of Barcelona. He noted that studies he has participated in have already shown that the walnut-supplemented diet had beneficial effects on blood pressure, systemic inflammation and endothelial function.

Other strengths of the study, he said, were that it recruited patients from two distinct locations and that it retained 90% of participants over 2 years (the study started out with 708 participants).

Christie Ballantyne, MD, concurred that the size and duration of the study are worth noting. “People always have questions about what they should eat,” said Dr. Ballantyne, chief of cardiology at Baylor College of Medicine and director of cardiovascular disease prevention at Methodist DeBakey Heart Center, both in Houston, said in an interview. “It’s very difficult to do nutritional studies. Most studies are small and short term, so it’s unusual to have study that’s large with 2 years of follow-up. This is a larger-than-usual study.”

Potential study limitations

Dr. Ros did acknowledge some limitations of the study. Participants weren’t blinded, the feeding setting wasn’t controlled, and participants were generally healthy and had average normal lipid profiles because they were taking statins, which may explain the modest lipid improvements in the study. “LDL cholesterol lowering by nuts is related to baseline levels, hence the reduction observed in our study was modest,” he said.

Additionally, because the study group was elderly, the results don’t apply to younger people. “Yet,” Dr. Ros added, “we know from many prior studies that nuts in general and walnuts in particular will lower blood cholesterol regardless of age.”

Dr. Ballantyne noted that the use of nuclear magnetic resonance spectroscopy to evaluate lipid levels involves a methodology that isn’t as systematic or as standardized as the typical lipid profile, and that different systems use proprietary software to interpret results. “That’s a little bit of an issue,” he said. “What exactly do the numbers mean?”

Overall, though, Dr. Ballantyne said the study is a significant addition to the literature. “The study is large, well done, and it confirms the benefits of something we’ve been telling patients is a good choice. It’s useful because there’s so much noise. It is important because there’s tremendous confusion and misinformation about what’s really healthy to eat.”

The study was supported by a grant from the California Walnut Commission (CWC), from which Dr. Ros and two coauthors received research funding through their institutions. Dr. Ros also reported receiving compensation from CWC and serves on a CWC advisory council. The other authors have no relationships to disclose. The WAHA study was supported by a grant from the CWC, from which Dr. Ros and some coinvestigators have received research funding through their institutions. Dr. Ballantyne has no relevant relationships to disclose.

Healthy elderly people who ate a walnut-supplemented diet for 2 years showed significant reductions in LDL cholesterol, according to a randomized study that used imaging to evaluate lipid changes.

©rootstocks/Thinkstock

“Regularly eating walnuts will lower your LDL cholesterol and improve the quality of LDL particles, rendering them less prone to enter the arterial wall and build up atherosclerosis, and this will occur without unwanted weight gain in spite of the high-fat – healthy vegetable fat, though – content of walnuts,” Emilio Ros, MD, PhD, senior author of the Walnuts and Healthy Aging (WAHA) study, said in an interview.

WAHA is a parallel-group, randomized, controlled trial that followed 636 patients over 2 years at centers in Loma Linda, Calif., and Barcelona. They were randomly assigned to either a walnut-free or walnut-supplemented diet, and every 2 months they were underwent nuclear magnetic resonance spectroscopy and recorded their compliance, toleration, medication changes, and body weight.

The researchers reported “significantly decreased” total cholesterol, LDL cholesterol and intermediate-density lipoprotein cholesterol, along with reductions in total LDL cholesterol particles and small LDL cholesterol particle number in patients on a walnut-supplemented diet, compared with controls. However, triglycerides and HDL cholesterol were unaffected.

Study results

The study reported mean reductions in the following lipid categories among what the researchers called the “walnut group”:

• Total cholesterol, –8.5 mg/dL (95% confidence interval, –11.2 to –5.4), a 4.4% mean reduction.
• LDL-C, –4.3 mg/dL (95% CI, –6.6 to –1.6), a 3.6% reduction.
• Intermediate-density lipoprotein cholesterol, –1.3 mg/dL (95% CI, –1.5 to –1.0] for a 16.8% reduction.
• Total LDL cholesterol particles, a reduction of 4.3%.
• Small LDL cholesterol particle number, a 6.1% decrease.

“WAHA is the largest and longest randomized nut trial to date, which overcomes power limitations of former trials, smaller and of shorter duration,” said Dr. Ros, of the lipid clinic, endocrinology, nutrition service at the Hospital Clinic Villarroel at the University of Barcelona. He noted that studies he has participated in have already shown that the walnut-supplemented diet had beneficial effects on blood pressure, systemic inflammation and endothelial function.

Other strengths of the study, he said, were that it recruited patients from two distinct locations and that it retained 90% of participants over 2 years (the study started out with 708 participants).

Christie Ballantyne, MD, concurred that the size and duration of the study are worth noting. “People always have questions about what they should eat,” said Dr. Ballantyne, chief of cardiology at Baylor College of Medicine and director of cardiovascular disease prevention at Methodist DeBakey Heart Center, both in Houston, said in an interview. “It’s very difficult to do nutritional studies. Most studies are small and short term, so it’s unusual to have study that’s large with 2 years of follow-up. This is a larger-than-usual study.”

Potential study limitations

Dr. Ros did acknowledge some limitations of the study. Participants weren’t blinded, the feeding setting wasn’t controlled, and participants were generally healthy and had average normal lipid profiles because they were taking statins, which may explain the modest lipid improvements in the study. “LDL cholesterol lowering by nuts is related to baseline levels, hence the reduction observed in our study was modest,” he said.

Additionally, because the study group was elderly, the results don’t apply to younger people. “Yet,” Dr. Ros added, “we know from many prior studies that nuts in general and walnuts in particular will lower blood cholesterol regardless of age.”

Dr. Ballantyne noted that the use of nuclear magnetic resonance spectroscopy to evaluate lipid levels involves a methodology that isn’t as systematic or as standardized as the typical lipid profile, and that different systems use proprietary software to interpret results. “That’s a little bit of an issue,” he said. “What exactly do the numbers mean?”

Overall, though, Dr. Ballantyne said the study is a significant addition to the literature. “The study is large, well done, and it confirms the benefits of something we’ve been telling patients is a good choice. It’s useful because there’s so much noise. It is important because there’s tremendous confusion and misinformation about what’s really healthy to eat.”

The study was supported by a grant from the California Walnut Commission (CWC), from which Dr. Ros and two coauthors received research funding through their institutions. Dr. Ros also reported receiving compensation from CWC and serves on a CWC advisory council. The other authors have no relationships to disclose. The WAHA study was supported by a grant from the CWC, from which Dr. Ros and some coinvestigators have received research funding through their institutions. Dr. Ballantyne has no relevant relationships to disclose.

Healthy elderly people who ate a walnut-supplemented diet for 2 years showed significant reductions in LDL cholesterol, according to a randomized study that used imaging to evaluate lipid changes.

©rootstocks/Thinkstock

“Regularly eating walnuts will lower your LDL cholesterol and improve the quality of LDL particles, rendering them less prone to enter the arterial wall and build up atherosclerosis, and this will occur without unwanted weight gain in spite of the high-fat – healthy vegetable fat, though – content of walnuts,” Emilio Ros, MD, PhD, senior author of the Walnuts and Healthy Aging (WAHA) study, said in an interview.

WAHA is a parallel-group, randomized, controlled trial that followed 636 patients over 2 years at centers in Loma Linda, Calif., and Barcelona. They were randomly assigned to either a walnut-free or walnut-supplemented diet, and every 2 months they were underwent nuclear magnetic resonance spectroscopy and recorded their compliance, toleration, medication changes, and body weight.

The researchers reported “significantly decreased” total cholesterol, LDL cholesterol and intermediate-density lipoprotein cholesterol, along with reductions in total LDL cholesterol particles and small LDL cholesterol particle number in patients on a walnut-supplemented diet, compared with controls. However, triglycerides and HDL cholesterol were unaffected.

Study results

The study reported mean reductions in the following lipid categories among what the researchers called the “walnut group”:

• Total cholesterol, –8.5 mg/dL (95% confidence interval, –11.2 to –5.4), a 4.4% mean reduction.
• LDL-C, –4.3 mg/dL (95% CI, –6.6 to –1.6), a 3.6% reduction.
• Intermediate-density lipoprotein cholesterol, –1.3 mg/dL (95% CI, –1.5 to –1.0] for a 16.8% reduction.
• Total LDL cholesterol particles, a reduction of 4.3%.
• Small LDL cholesterol particle number, a 6.1% decrease.

“WAHA is the largest and longest randomized nut trial to date, which overcomes power limitations of former trials, smaller and of shorter duration,” said Dr. Ros, of the lipid clinic, endocrinology, nutrition service at the Hospital Clinic Villarroel at the University of Barcelona. He noted that studies he has participated in have already shown that the walnut-supplemented diet had beneficial effects on blood pressure, systemic inflammation and endothelial function.

Other strengths of the study, he said, were that it recruited patients from two distinct locations and that it retained 90% of participants over 2 years (the study started out with 708 participants).

Christie Ballantyne, MD, concurred that the size and duration of the study are worth noting. “People always have questions about what they should eat,” said Dr. Ballantyne, chief of cardiology at Baylor College of Medicine and director of cardiovascular disease prevention at Methodist DeBakey Heart Center, both in Houston, said in an interview. “It’s very difficult to do nutritional studies. Most studies are small and short term, so it’s unusual to have study that’s large with 2 years of follow-up. This is a larger-than-usual study.”

Potential study limitations

Dr. Ros did acknowledge some limitations of the study. Participants weren’t blinded, the feeding setting wasn’t controlled, and participants were generally healthy and had average normal lipid profiles because they were taking statins, which may explain the modest lipid improvements in the study. “LDL cholesterol lowering by nuts is related to baseline levels, hence the reduction observed in our study was modest,” he said.

Additionally, because the study group was elderly, the results don’t apply to younger people. “Yet,” Dr. Ros added, “we know from many prior studies that nuts in general and walnuts in particular will lower blood cholesterol regardless of age.”

Dr. Ballantyne noted that the use of nuclear magnetic resonance spectroscopy to evaluate lipid levels involves a methodology that isn’t as systematic or as standardized as the typical lipid profile, and that different systems use proprietary software to interpret results. “That’s a little bit of an issue,” he said. “What exactly do the numbers mean?”

Overall, though, Dr. Ballantyne said the study is a significant addition to the literature. “The study is large, well done, and it confirms the benefits of something we’ve been telling patients is a good choice. It’s useful because there’s so much noise. It is important because there’s tremendous confusion and misinformation about what’s really healthy to eat.”

The study was supported by a grant from the California Walnut Commission (CWC), from which Dr. Ros and two coauthors received research funding through their institutions. Dr. Ros also reported receiving compensation from CWC and serves on a CWC advisory council. The other authors have no relationships to disclose. The WAHA study was supported by a grant from the CWC, from which Dr. Ros and some coinvestigators have received research funding through their institutions. Dr. Ballantyne has no relevant relationships to disclose.

Dapagliflozin might reduce the risk for ventricular arrhythmias and sudden death in patients with heart failure and reduced ejection fraction (HFrEF), a post hoc analysis of the DAPA-HF trial suggests.

The addition of dapagliflozin to standard therapy reduced the relative risk for the primary composite endpoint of any serious ventricular arrhythmia, resuscitated cardiac arrest, or sudden death by 21%, compared with placebo (hazard ratio, 0.79; 95% confidence interval, 0.63-0.99). The absolute risk reduction was 1.5% (5.9% vs. 7.4%).

The benefit was consistent in a competing-risks analysis that included all-cause mortality (HR, 0.80; P = .043) and across the individual components of the composite outcome, James Curtain, MD, Cardiovascular Research Centre of Glasgow, said at the annual congress of the European Society of Cardiology.

As previously reported from the main trial, treatment with the sodium-glucose cotransporter 2 (SGLT2) inhibitor cut the primary endpoint of cardiovascular death or worsening heart failure by 26% among 4,744 patients with HFrEF and in New York Heart Association functional class 2-4.

Cochair of the late-breaking science session, Lars Lund, MD, Karolinska Institute, Stockholm, pointed out that dapagliflozin reduced sudden cardiac deaths and related events to an extent similar to that observed for cardiovascular deaths, total mortality, and the main trial’s primary endpoint.

“So does that mean it has any particular effect on arrhythmic events or does it mean, such as a beta-blocker, for example, [it] reduces calcium transience and improves handling of calcium, or does it have an effect simply by improving heart failure?” he asked.

Dr. Curtain replied they are still trying to understand the effects of this new class of drug but that studies have shown dapagliflozin and other SGLT2 inhibitors have favorable effects on adverse cardiac remodeling, which contributes to sudden death and ventricular arrhythmia. They’ve also been shown to reduce cardiac chamber size, left ventricular hypertrophy, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels over time, consistent with a reduction in myocardial wall stress. “So it could indeed be one of several mechanisms by which they may exert a beneficial cardiac effect.”

Speaking with this news organization, Dr. Curtain pointed out that the Kaplan-Meier curves for the composite outcome began to separate early on, but that the clearest separation was after 9 months, suggestive of a positive action on adverse cardiac remodeling over time.

“This would improve the patients’ heart failure situation, but also thick ventricles are a key risk factor for the occurrence of sudden death and ventricular arrhythmias,” he said. “The effects on adverse cardiac remodeling, given its plausibility in terms of our Kaplan-Meier curves, are one [mechanism] that I’d look to in the first instance, but I’m sure there are more than one actions at play.”

According to the new analysis, the primary outcome occurred in 315 (6.6%) patients; there were 203 adjudicated sudden deaths (64%), 104 investigator-reported ventricular arrhythmias (33%), and 8 resuscitated cardiac arrests (3%). Independent predictors of the primary outcome were higher NT-proBNP levels (odds ratio, 1.54), previous ventricular arrhythmia (OR, 1.93), previous myocardial infarction (OR, 1.42), male sex (OR, 1.53), and higher body mass index (OR, 1.03).

A version of this article first appeared on Medscape.com.

Dapagliflozin might reduce the risk for ventricular arrhythmias and sudden death in patients with heart failure and reduced ejection fraction (HFrEF), a post hoc analysis of the DAPA-HF trial suggests.

The addition of dapagliflozin to standard therapy reduced the relative risk for the primary composite endpoint of any serious ventricular arrhythmia, resuscitated cardiac arrest, or sudden death by 21%, compared with placebo (hazard ratio, 0.79; 95% confidence interval, 0.63-0.99). The absolute risk reduction was 1.5% (5.9% vs. 7.4%).

The benefit was consistent in a competing-risks analysis that included all-cause mortality (HR, 0.80; P = .043) and across the individual components of the composite outcome, James Curtain, MD, Cardiovascular Research Centre of Glasgow, said at the annual congress of the European Society of Cardiology.

As previously reported from the main trial, treatment with the sodium-glucose cotransporter 2 (SGLT2) inhibitor cut the primary endpoint of cardiovascular death or worsening heart failure by 26% among 4,744 patients with HFrEF and in New York Heart Association functional class 2-4.

Cochair of the late-breaking science session, Lars Lund, MD, Karolinska Institute, Stockholm, pointed out that dapagliflozin reduced sudden cardiac deaths and related events to an extent similar to that observed for cardiovascular deaths, total mortality, and the main trial’s primary endpoint.

“So does that mean it has any particular effect on arrhythmic events or does it mean, such as a beta-blocker, for example, [it] reduces calcium transience and improves handling of calcium, or does it have an effect simply by improving heart failure?” he asked.

Dr. Curtain replied they are still trying to understand the effects of this new class of drug but that studies have shown dapagliflozin and other SGLT2 inhibitors have favorable effects on adverse cardiac remodeling, which contributes to sudden death and ventricular arrhythmia. They’ve also been shown to reduce cardiac chamber size, left ventricular hypertrophy, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels over time, consistent with a reduction in myocardial wall stress. “So it could indeed be one of several mechanisms by which they may exert a beneficial cardiac effect.”

Speaking with this news organization, Dr. Curtain pointed out that the Kaplan-Meier curves for the composite outcome began to separate early on, but that the clearest separation was after 9 months, suggestive of a positive action on adverse cardiac remodeling over time.

“This would improve the patients’ heart failure situation, but also thick ventricles are a key risk factor for the occurrence of sudden death and ventricular arrhythmias,” he said. “The effects on adverse cardiac remodeling, given its plausibility in terms of our Kaplan-Meier curves, are one [mechanism] that I’d look to in the first instance, but I’m sure there are more than one actions at play.”

According to the new analysis, the primary outcome occurred in 315 (6.6%) patients; there were 203 adjudicated sudden deaths (64%), 104 investigator-reported ventricular arrhythmias (33%), and 8 resuscitated cardiac arrests (3%). Independent predictors of the primary outcome were higher NT-proBNP levels (odds ratio, 1.54), previous ventricular arrhythmia (OR, 1.93), previous myocardial infarction (OR, 1.42), male sex (OR, 1.53), and higher body mass index (OR, 1.03).

A version of this article first appeared on Medscape.com.

Dapagliflozin might reduce the risk for ventricular arrhythmias and sudden death in patients with heart failure and reduced ejection fraction (HFrEF), a post hoc analysis of the DAPA-HF trial suggests.

The addition of dapagliflozin to standard therapy reduced the relative risk for the primary composite endpoint of any serious ventricular arrhythmia, resuscitated cardiac arrest, or sudden death by 21%, compared with placebo (hazard ratio, 0.79; 95% confidence interval, 0.63-0.99). The absolute risk reduction was 1.5% (5.9% vs. 7.4%).

The benefit was consistent in a competing-risks analysis that included all-cause mortality (HR, 0.80; P = .043) and across the individual components of the composite outcome, James Curtain, MD, Cardiovascular Research Centre of Glasgow, said at the annual congress of the European Society of Cardiology.

As previously reported from the main trial, treatment with the sodium-glucose cotransporter 2 (SGLT2) inhibitor cut the primary endpoint of cardiovascular death or worsening heart failure by 26% among 4,744 patients with HFrEF and in New York Heart Association functional class 2-4.

Cochair of the late-breaking science session, Lars Lund, MD, Karolinska Institute, Stockholm, pointed out that dapagliflozin reduced sudden cardiac deaths and related events to an extent similar to that observed for cardiovascular deaths, total mortality, and the main trial’s primary endpoint.

“So does that mean it has any particular effect on arrhythmic events or does it mean, such as a beta-blocker, for example, [it] reduces calcium transience and improves handling of calcium, or does it have an effect simply by improving heart failure?” he asked.

Dr. Curtain replied they are still trying to understand the effects of this new class of drug but that studies have shown dapagliflozin and other SGLT2 inhibitors have favorable effects on adverse cardiac remodeling, which contributes to sudden death and ventricular arrhythmia. They’ve also been shown to reduce cardiac chamber size, left ventricular hypertrophy, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels over time, consistent with a reduction in myocardial wall stress. “So it could indeed be one of several mechanisms by which they may exert a beneficial cardiac effect.”

Speaking with this news organization, Dr. Curtain pointed out that the Kaplan-Meier curves for the composite outcome began to separate early on, but that the clearest separation was after 9 months, suggestive of a positive action on adverse cardiac remodeling over time.

“This would improve the patients’ heart failure situation, but also thick ventricles are a key risk factor for the occurrence of sudden death and ventricular arrhythmias,” he said. “The effects on adverse cardiac remodeling, given its plausibility in terms of our Kaplan-Meier curves, are one [mechanism] that I’d look to in the first instance, but I’m sure there are more than one actions at play.”

According to the new analysis, the primary outcome occurred in 315 (6.6%) patients; there were 203 adjudicated sudden deaths (64%), 104 investigator-reported ventricular arrhythmias (33%), and 8 resuscitated cardiac arrests (3%). Independent predictors of the primary outcome were higher NT-proBNP levels (odds ratio, 1.54), previous ventricular arrhythmia (OR, 1.93), previous myocardial infarction (OR, 1.42), male sex (OR, 1.53), and higher body mass index (OR, 1.03).

A version of this article first appeared on Medscape.com.

Updated August 30, 2021

The SGLT2 inhibitor empagliflozin achieved in EMPEROR-Preserved what no other agent could previously do: unequivocally cut the incidence of cardiovascular death or hospitalization in patients with heart failure and preserved ejection fraction (HFpEF).

MDedge News

Treatment with empagliflozin (Jardiance) led to a significant 21% relative reduction in the rate of cardiovascular death or hospitalization for heart failure (HHF), compared with placebo, among 5,988 randomized patients with HFpEF during a median 26 months of follow-up, proving that patients with HFpEF finally have a treatment that gives them clinically meaningful benefit, and paving the way to an abrupt change in management of these patients, experts said.

“This is the first trial to show unequivocal benefits of any drug on major heart failure outcomes in patients with HFpEF,” Stefan D. Anker, MD, PhD, declared at the virtual annual congress of the European Society of Cardiology.

The 21% relative reduction, which reflected a cut in the absolute rate of the trial’s primary composite endpoint of 3.3% compared with placebo, was driven mainly by a significant 27% relative reduction in the incidence of HHF (P < .001). Empagliflozin treatment, on top of standard therapy for patients with HFpEF, also resulted in a nonsignificant 9% relative risk reduction in the incidence of cardiovascular death, but it had no discernible impact on the rate of death from any cause, said Dr. Anker, professor of cardiology at Charité Medical University in Berlin.

Concurrently with his talk at the meeting, the results were published online in the New England Journal of Medicine.
 

Practice will change ‘quickly’

“This will definitely change our practice, and quite quickly,” said Carlos Aguiar, MD, chair of the Advanced Heart Failure and Heart Transplantation Unit at Hospital Santa Cruz in Carnaxide, Portugal, who was not involved in the study.

Transition to routine use of empagliflozin in patients with HFpEF should be swift because it has already become a mainstay of treatment for patients with heart failure with reduced ejection fraction (HFrEF) based on evidence for empagliflozin in EMPEROR-Reduced. A second sodium-glucose cotransporter 2 (SGLT2 ) inhibitor, dapagliflozin (Farxiga), is also an option for treating HFrEF based on results in the DAPA-HF trial, and the DELIVER trial, still in progress, is testing dapagliflozin as a HFpEF treatment in about 6,000 patients, with results expected in 2022.

About half of the patients in EMPEROR-Preserved had diabetes, and the treatment effects on HFpEF were similar regardless of patients’ diabetes status. Empagliflozin, like other members of the SGLT2 inhibitor class, boosts urinary excretion of glucose and received initial regulatory approval as an agent for glycemic control in patients with type 2 diabetes. Empagliflozin also has U.S.-approved marketing indications for treating patients with HFrEF whether or not they also have diabetes, and for reducing cardiovascular death in patients with type 2 diabetes and cardiovascular disease.

“We already use this drug class in cardiovascular medicine and to treat patients with type 2 diabetes, and we have been eager to find a treatment for patients with HFpEF. This is something that will be really significant,” said Dr. Aguiar.

Heart failure clinicians have “become familiar prescribing” SGLT2 inhibitors following approval of HFrEF indications for some of these agents, noted Mary Norine Walsh, MD, a heart failure specialist with Ascension Medical Group in Indianapolis. The new results “are good news because there have been so few options” for patients with HFpEF, she said in an interview.

EMPEROR-Preserved “is the first phase 3 clinical trial that exclusively enrolled patients with heart failure and an ejection fraction of more than 40% to meet its primary outcome,” and the results “represent a major win against a medical condition that had previously proven formidable,” Mark H. Drazner, MD, said in an editorial that accompanied the published results.

The trial’s findings “should contribute to a change in clinical practice given the paucity of therapeutic options available for patients with HFpEF,” wrote Dr. Drazner, a heart failure specialist who is professor and clinical chief of cardiology at UT Southwestern Medical Center in Dallas.

Theresa A, McDonagh, MD, MBChB, who chaired the panel that just released revised guidelines from the European Society of Cardiology for managing patients with heart failure, predicted that empagliflozin treatment for patients with HFpEF will soon show up in guidelines. It will likely receive a “should be considered” ranking despite being a single study because of the impressive size of the treatment effect and lack of well-supported alternative treatments, she commented as a discussant of the trial during its presentation at the congress. If the DELIVER trial with dapagliflozin shows a similar effect, the recommendation would likely become even stronger, added Dr. McDonagh, a heart failure specialist and professor of cardiology at King’s College, London.

More women enrolled than ever before

EMPEROR-Preserved enrolled adults with chronic HFpEF in New York Heart Association functional class II-IV and a left ventricular ejection fraction greater than 40% starting in 2017 at more than 600 sites in more than 20 countries worldwide including the United States. As background therapy, more than 80% of patients received treatment with either an ACE inhibitor or angiotensin receptor blocker (in some instances in the form of sacubitril/valsartan), more than 80% were on a beta-blocker, and about a third were taking a mineralocorticoid receptor antagonist, making them “very well treated HFpEF patients,” Dr. Anker said.

One of the most notable features of enrollment was that 45% of participants were women, giving this trial the highest inclusion of women compared with all prior studies in patients with HFpEF or with HFrEF, said Dr. Walsh. “HFpEF is very prevalent in woman,” she noted, and having this high participation rate of women in the study increases its relevance to these patients. “It’s important to be able to tell women that patients like you were in the study so we can more easily apply the lessons from the trial to you. That can’t be stressed enough,” she said.

The primary outcome occurred in 415 (13.8%) of the 2,997 patients in the empagliflozin group and in 511 (17.1%) of 2,991 patients who received placebo (hazard ratio, 0.79; 95% confidence interval, 0.69-0.90; P < .001).

The study showed a safety profile consistent with prior experience with empagliflozin, Dr. Anker added.

Pooling EMPEROR-Preserved with EMPEROR-Reduced

The investigators who ran EMPEROR-Preserved designed the trial to closely parallel the EMPEROR-Reduced trial in patients with HFrEF, and they included a prespecified analysis (EMPEROR-Pooled) that combined the more than 9,700 patients in the two studies. This showed a consistent and robust benefit from empagliflozin for reducing HHF across a wide spectrum of patients with heart failure, ranging from patients with left ventricular ejection fractions of less than 25% to patients with ejection fractions as high as 64%. However, the analysis also showed that patients with ejection fractions of 65% or greater received no discernible benefit from empagliflozin, Milton Packer, MD, reported in a separate talk at the congress.

MDedge News

“The findings demonstrate the benefits of empagliflozin across a broad range of patients with heart failure who have ejection fractions of less than 60%-65%,” said Dr. Packer, a researcher at Baylor University Medical Center in Dallas.

This apparent attenuation of an effect at higher ejection fractions “has been observed in other HFpEF trials, most recently in the PARAGON-HF trial” of sacubitril/valsartan (Entresto), he noted. Additional analyses led by Dr. Packer showed that in patients with ejection fractions below 65% the HHF benefit from empagliflozin consistently surpassed the benefit seen with sacubitril/valsartan in PARAGON-HF. But he recommended using both drugs in patients with HFpEF and an ejection fraction up to about 60%.

“If I had a patient with HFpEF I would use both drugs as well as beta-blockers and mineralocorticoid receptor antagonists,” he said during a press briefing.

Another finding from analysis of the EMPEROR-Reduced and EMPEROR-Preserved trials together was that patients with reduced ejection fractions showed a significant 49% relative reduction in the incidence of serious renal outcomes, but this effect was completely blunted in EMPEROR-Preserved.

“Ejection fraction influences the effects of empagliflozin on major renal outcomes,” concluded Dr. Packer in a report on this analysis published simultaneously with the main EMPEROR-Preserved findings (N Engl J Med. 2021 Aug 27. doi: 10.1056/NEJMc2112411). “These data from the EMPEROR trials are unique. We have no comparable data” from any of the other reported studies of SGLT2 inhibitors,” he said.

EMPEROR-Preserved was sponsored by Boehringer Ingelheim and by Eli Lilly, the two companies that jointly market empagliflozin (Jardiance). Dr. Anker has received personal fees from Boehringer Ingelheim and from several other companies, and he has received grants and personal fees from Abbott Vascular and Vifor. Dr. Packer has received consulting fees from Boehringer Ingelheim and from numerous other companies. Dr. McDonagh has has recent financial relationships with AstraZeneca, Cprpus, Novartis, Pfizer, and Vifor. Dr. Aguiar and Dr. Walsh had no disclosures.

[email protected]

Updated August 30, 2021

The SGLT2 inhibitor empagliflozin achieved in EMPEROR-Preserved what no other agent could previously do: unequivocally cut the incidence of cardiovascular death or hospitalization in patients with heart failure and preserved ejection fraction (HFpEF).

MDedge News

Treatment with empagliflozin (Jardiance) led to a significant 21% relative reduction in the rate of cardiovascular death or hospitalization for heart failure (HHF), compared with placebo, among 5,988 randomized patients with HFpEF during a median 26 months of follow-up, proving that patients with HFpEF finally have a treatment that gives them clinically meaningful benefit, and paving the way to an abrupt change in management of these patients, experts said.

“This is the first trial to show unequivocal benefits of any drug on major heart failure outcomes in patients with HFpEF,” Stefan D. Anker, MD, PhD, declared at the virtual annual congress of the European Society of Cardiology.

The 21% relative reduction, which reflected a cut in the absolute rate of the trial’s primary composite endpoint of 3.3% compared with placebo, was driven mainly by a significant 27% relative reduction in the incidence of HHF (P < .001). Empagliflozin treatment, on top of standard therapy for patients with HFpEF, also resulted in a nonsignificant 9% relative risk reduction in the incidence of cardiovascular death, but it had no discernible impact on the rate of death from any cause, said Dr. Anker, professor of cardiology at Charité Medical University in Berlin.

Concurrently with his talk at the meeting, the results were published online in the New England Journal of Medicine.
 

Practice will change ‘quickly’

“This will definitely change our practice, and quite quickly,” said Carlos Aguiar, MD, chair of the Advanced Heart Failure and Heart Transplantation Unit at Hospital Santa Cruz in Carnaxide, Portugal, who was not involved in the study.

Transition to routine use of empagliflozin in patients with HFpEF should be swift because it has already become a mainstay of treatment for patients with heart failure with reduced ejection fraction (HFrEF) based on evidence for empagliflozin in EMPEROR-Reduced. A second sodium-glucose cotransporter 2 (SGLT2 ) inhibitor, dapagliflozin (Farxiga), is also an option for treating HFrEF based on results in the DAPA-HF trial, and the DELIVER trial, still in progress, is testing dapagliflozin as a HFpEF treatment in about 6,000 patients, with results expected in 2022.

About half of the patients in EMPEROR-Preserved had diabetes, and the treatment effects on HFpEF were similar regardless of patients’ diabetes status. Empagliflozin, like other members of the SGLT2 inhibitor class, boosts urinary excretion of glucose and received initial regulatory approval as an agent for glycemic control in patients with type 2 diabetes. Empagliflozin also has U.S.-approved marketing indications for treating patients with HFrEF whether or not they also have diabetes, and for reducing cardiovascular death in patients with type 2 diabetes and cardiovascular disease.

“We already use this drug class in cardiovascular medicine and to treat patients with type 2 diabetes, and we have been eager to find a treatment for patients with HFpEF. This is something that will be really significant,” said Dr. Aguiar.

Heart failure clinicians have “become familiar prescribing” SGLT2 inhibitors following approval of HFrEF indications for some of these agents, noted Mary Norine Walsh, MD, a heart failure specialist with Ascension Medical Group in Indianapolis. The new results “are good news because there have been so few options” for patients with HFpEF, she said in an interview.

EMPEROR-Preserved “is the first phase 3 clinical trial that exclusively enrolled patients with heart failure and an ejection fraction of more than 40% to meet its primary outcome,” and the results “represent a major win against a medical condition that had previously proven formidable,” Mark H. Drazner, MD, said in an editorial that accompanied the published results.

The trial’s findings “should contribute to a change in clinical practice given the paucity of therapeutic options available for patients with HFpEF,” wrote Dr. Drazner, a heart failure specialist who is professor and clinical chief of cardiology at UT Southwestern Medical Center in Dallas.

Theresa A, McDonagh, MD, MBChB, who chaired the panel that just released revised guidelines from the European Society of Cardiology for managing patients with heart failure, predicted that empagliflozin treatment for patients with HFpEF will soon show up in guidelines. It will likely receive a “should be considered” ranking despite being a single study because of the impressive size of the treatment effect and lack of well-supported alternative treatments, she commented as a discussant of the trial during its presentation at the congress. If the DELIVER trial with dapagliflozin shows a similar effect, the recommendation would likely become even stronger, added Dr. McDonagh, a heart failure specialist and professor of cardiology at King’s College, London.

More women enrolled than ever before

EMPEROR-Preserved enrolled adults with chronic HFpEF in New York Heart Association functional class II-IV and a left ventricular ejection fraction greater than 40% starting in 2017 at more than 600 sites in more than 20 countries worldwide including the United States. As background therapy, more than 80% of patients received treatment with either an ACE inhibitor or angiotensin receptor blocker (in some instances in the form of sacubitril/valsartan), more than 80% were on a beta-blocker, and about a third were taking a mineralocorticoid receptor antagonist, making them “very well treated HFpEF patients,” Dr. Anker said.

One of the most notable features of enrollment was that 45% of participants were women, giving this trial the highest inclusion of women compared with all prior studies in patients with HFpEF or with HFrEF, said Dr. Walsh. “HFpEF is very prevalent in woman,” she noted, and having this high participation rate of women in the study increases its relevance to these patients. “It’s important to be able to tell women that patients like you were in the study so we can more easily apply the lessons from the trial to you. That can’t be stressed enough,” she said.

The primary outcome occurred in 415 (13.8%) of the 2,997 patients in the empagliflozin group and in 511 (17.1%) of 2,991 patients who received placebo (hazard ratio, 0.79; 95% confidence interval, 0.69-0.90; P < .001).

The study showed a safety profile consistent with prior experience with empagliflozin, Dr. Anker added.

Pooling EMPEROR-Preserved with EMPEROR-Reduced

The investigators who ran EMPEROR-Preserved designed the trial to closely parallel the EMPEROR-Reduced trial in patients with HFrEF, and they included a prespecified analysis (EMPEROR-Pooled) that combined the more than 9,700 patients in the two studies. This showed a consistent and robust benefit from empagliflozin for reducing HHF across a wide spectrum of patients with heart failure, ranging from patients with left ventricular ejection fractions of less than 25% to patients with ejection fractions as high as 64%. However, the analysis also showed that patients with ejection fractions of 65% or greater received no discernible benefit from empagliflozin, Milton Packer, MD, reported in a separate talk at the congress.

MDedge News

“The findings demonstrate the benefits of empagliflozin across a broad range of patients with heart failure who have ejection fractions of less than 60%-65%,” said Dr. Packer, a researcher at Baylor University Medical Center in Dallas.

This apparent attenuation of an effect at higher ejection fractions “has been observed in other HFpEF trials, most recently in the PARAGON-HF trial” of sacubitril/valsartan (Entresto), he noted. Additional analyses led by Dr. Packer showed that in patients with ejection fractions below 65% the HHF benefit from empagliflozin consistently surpassed the benefit seen with sacubitril/valsartan in PARAGON-HF. But he recommended using both drugs in patients with HFpEF and an ejection fraction up to about 60%.

“If I had a patient with HFpEF I would use both drugs as well as beta-blockers and mineralocorticoid receptor antagonists,” he said during a press briefing.

Another finding from analysis of the EMPEROR-Reduced and EMPEROR-Preserved trials together was that patients with reduced ejection fractions showed a significant 49% relative reduction in the incidence of serious renal outcomes, but this effect was completely blunted in EMPEROR-Preserved.

“Ejection fraction influences the effects of empagliflozin on major renal outcomes,” concluded Dr. Packer in a report on this analysis published simultaneously with the main EMPEROR-Preserved findings (N Engl J Med. 2021 Aug 27. doi: 10.1056/NEJMc2112411). “These data from the EMPEROR trials are unique. We have no comparable data” from any of the other reported studies of SGLT2 inhibitors,” he said.

EMPEROR-Preserved was sponsored by Boehringer Ingelheim and by Eli Lilly, the two companies that jointly market empagliflozin (Jardiance). Dr. Anker has received personal fees from Boehringer Ingelheim and from several other companies, and he has received grants and personal fees from Abbott Vascular and Vifor. Dr. Packer has received consulting fees from Boehringer Ingelheim and from numerous other companies. Dr. McDonagh has has recent financial relationships with AstraZeneca, Cprpus, Novartis, Pfizer, and Vifor. Dr. Aguiar and Dr. Walsh had no disclosures.

[email protected]

Updated August 30, 2021

The SGLT2 inhibitor empagliflozin achieved in EMPEROR-Preserved what no other agent could previously do: unequivocally cut the incidence of cardiovascular death or hospitalization in patients with heart failure and preserved ejection fraction (HFpEF).

MDedge News

Treatment with empagliflozin (Jardiance) led to a significant 21% relative reduction in the rate of cardiovascular death or hospitalization for heart failure (HHF), compared with placebo, among 5,988 randomized patients with HFpEF during a median 26 months of follow-up, proving that patients with HFpEF finally have a treatment that gives them clinically meaningful benefit, and paving the way to an abrupt change in management of these patients, experts said.

“This is the first trial to show unequivocal benefits of any drug on major heart failure outcomes in patients with HFpEF,” Stefan D. Anker, MD, PhD, declared at the virtual annual congress of the European Society of Cardiology.

The 21% relative reduction, which reflected a cut in the absolute rate of the trial’s primary composite endpoint of 3.3% compared with placebo, was driven mainly by a significant 27% relative reduction in the incidence of HHF (P < .001). Empagliflozin treatment, on top of standard therapy for patients with HFpEF, also resulted in a nonsignificant 9% relative risk reduction in the incidence of cardiovascular death, but it had no discernible impact on the rate of death from any cause, said Dr. Anker, professor of cardiology at Charité Medical University in Berlin.

Concurrently with his talk at the meeting, the results were published online in the New England Journal of Medicine.
 

Practice will change ‘quickly’

“This will definitely change our practice, and quite quickly,” said Carlos Aguiar, MD, chair of the Advanced Heart Failure and Heart Transplantation Unit at Hospital Santa Cruz in Carnaxide, Portugal, who was not involved in the study.

Transition to routine use of empagliflozin in patients with HFpEF should be swift because it has already become a mainstay of treatment for patients with heart failure with reduced ejection fraction (HFrEF) based on evidence for empagliflozin in EMPEROR-Reduced. A second sodium-glucose cotransporter 2 (SGLT2 ) inhibitor, dapagliflozin (Farxiga), is also an option for treating HFrEF based on results in the DAPA-HF trial, and the DELIVER trial, still in progress, is testing dapagliflozin as a HFpEF treatment in about 6,000 patients, with results expected in 2022.

About half of the patients in EMPEROR-Preserved had diabetes, and the treatment effects on HFpEF were similar regardless of patients’ diabetes status. Empagliflozin, like other members of the SGLT2 inhibitor class, boosts urinary excretion of glucose and received initial regulatory approval as an agent for glycemic control in patients with type 2 diabetes. Empagliflozin also has U.S.-approved marketing indications for treating patients with HFrEF whether or not they also have diabetes, and for reducing cardiovascular death in patients with type 2 diabetes and cardiovascular disease.

“We already use this drug class in cardiovascular medicine and to treat patients with type 2 diabetes, and we have been eager to find a treatment for patients with HFpEF. This is something that will be really significant,” said Dr. Aguiar.

Heart failure clinicians have “become familiar prescribing” SGLT2 inhibitors following approval of HFrEF indications for some of these agents, noted Mary Norine Walsh, MD, a heart failure specialist with Ascension Medical Group in Indianapolis. The new results “are good news because there have been so few options” for patients with HFpEF, she said in an interview.

EMPEROR-Preserved “is the first phase 3 clinical trial that exclusively enrolled patients with heart failure and an ejection fraction of more than 40% to meet its primary outcome,” and the results “represent a major win against a medical condition that had previously proven formidable,” Mark H. Drazner, MD, said in an editorial that accompanied the published results.

The trial’s findings “should contribute to a change in clinical practice given the paucity of therapeutic options available for patients with HFpEF,” wrote Dr. Drazner, a heart failure specialist who is professor and clinical chief of cardiology at UT Southwestern Medical Center in Dallas.

Theresa A, McDonagh, MD, MBChB, who chaired the panel that just released revised guidelines from the European Society of Cardiology for managing patients with heart failure, predicted that empagliflozin treatment for patients with HFpEF will soon show up in guidelines. It will likely receive a “should be considered” ranking despite being a single study because of the impressive size of the treatment effect and lack of well-supported alternative treatments, she commented as a discussant of the trial during its presentation at the congress. If the DELIVER trial with dapagliflozin shows a similar effect, the recommendation would likely become even stronger, added Dr. McDonagh, a heart failure specialist and professor of cardiology at King’s College, London.

More women enrolled than ever before

EMPEROR-Preserved enrolled adults with chronic HFpEF in New York Heart Association functional class II-IV and a left ventricular ejection fraction greater than 40% starting in 2017 at more than 600 sites in more than 20 countries worldwide including the United States. As background therapy, more than 80% of patients received treatment with either an ACE inhibitor or angiotensin receptor blocker (in some instances in the form of sacubitril/valsartan), more than 80% were on a beta-blocker, and about a third were taking a mineralocorticoid receptor antagonist, making them “very well treated HFpEF patients,” Dr. Anker said.

One of the most notable features of enrollment was that 45% of participants were women, giving this trial the highest inclusion of women compared with all prior studies in patients with HFpEF or with HFrEF, said Dr. Walsh. “HFpEF is very prevalent in woman,” she noted, and having this high participation rate of women in the study increases its relevance to these patients. “It’s important to be able to tell women that patients like you were in the study so we can more easily apply the lessons from the trial to you. That can’t be stressed enough,” she said.

The primary outcome occurred in 415 (13.8%) of the 2,997 patients in the empagliflozin group and in 511 (17.1%) of 2,991 patients who received placebo (hazard ratio, 0.79; 95% confidence interval, 0.69-0.90; P < .001).

The study showed a safety profile consistent with prior experience with empagliflozin, Dr. Anker added.

Pooling EMPEROR-Preserved with EMPEROR-Reduced

The investigators who ran EMPEROR-Preserved designed the trial to closely parallel the EMPEROR-Reduced trial in patients with HFrEF, and they included a prespecified analysis (EMPEROR-Pooled) that combined the more than 9,700 patients in the two studies. This showed a consistent and robust benefit from empagliflozin for reducing HHF across a wide spectrum of patients with heart failure, ranging from patients with left ventricular ejection fractions of less than 25% to patients with ejection fractions as high as 64%. However, the analysis also showed that patients with ejection fractions of 65% or greater received no discernible benefit from empagliflozin, Milton Packer, MD, reported in a separate talk at the congress.

MDedge News

“The findings demonstrate the benefits of empagliflozin across a broad range of patients with heart failure who have ejection fractions of less than 60%-65%,” said Dr. Packer, a researcher at Baylor University Medical Center in Dallas.

This apparent attenuation of an effect at higher ejection fractions “has been observed in other HFpEF trials, most recently in the PARAGON-HF trial” of sacubitril/valsartan (Entresto), he noted. Additional analyses led by Dr. Packer showed that in patients with ejection fractions below 65% the HHF benefit from empagliflozin consistently surpassed the benefit seen with sacubitril/valsartan in PARAGON-HF. But he recommended using both drugs in patients with HFpEF and an ejection fraction up to about 60%.

“If I had a patient with HFpEF I would use both drugs as well as beta-blockers and mineralocorticoid receptor antagonists,” he said during a press briefing.

Another finding from analysis of the EMPEROR-Reduced and EMPEROR-Preserved trials together was that patients with reduced ejection fractions showed a significant 49% relative reduction in the incidence of serious renal outcomes, but this effect was completely blunted in EMPEROR-Preserved.

“Ejection fraction influences the effects of empagliflozin on major renal outcomes,” concluded Dr. Packer in a report on this analysis published simultaneously with the main EMPEROR-Preserved findings (N Engl J Med. 2021 Aug 27. doi: 10.1056/NEJMc2112411). “These data from the EMPEROR trials are unique. We have no comparable data” from any of the other reported studies of SGLT2 inhibitors,” he said.

EMPEROR-Preserved was sponsored by Boehringer Ingelheim and by Eli Lilly, the two companies that jointly market empagliflozin (Jardiance). Dr. Anker has received personal fees from Boehringer Ingelheim and from several other companies, and he has received grants and personal fees from Abbott Vascular and Vifor. Dr. Packer has received consulting fees from Boehringer Ingelheim and from numerous other companies. Dr. McDonagh has has recent financial relationships with AstraZeneca, Cprpus, Novartis, Pfizer, and Vifor. Dr. Aguiar and Dr. Walsh had no disclosures.

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