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SNOWMASS, COLO. – The oral sodium-glucose cotransporter-2 (SGLT2) inhibitors are the focus of a slew of ongoing phase 3 clinical trials in patients with symptomatic heart failure but no diabetes.
“We have a wide array of exciting opportunities to modify cardiovascular risk with agents that were initially developed for the therapy of diabetes. I think we’re increasingly moving to an age where these agents are actually cardiovascular drugs that happen to lower blood glucose, rather than the other way around, which is how they were initially conceived,” Akshay S. Desai, MD, observed at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
These are each multi-thousand-patient trials, variously due to be completed in 2019-2021. Of note, several of them are restricted to nondiabetic patients with heart failure with preserved ejection fraction (HFpEF), a common, serious, understudied, extremely high-cost disease sorely in need of effective pharmacotherapies, added Dr. Desai, director of the cardiomyopathy and heart failure program at Brigham and Women’s Hospital and a cardiologist at Harvard Medical School, Boston.
All of these placebo-controlled trials have as their composite primary endpoint cardiovascular death and heart failure hospitalization.
EMPEROR-Preserved has randomized 4,126 patients with HFpEF to empagliflozin (Jardiance) or placebo, while EMPEROR-Reduced involves 2,850 patients with heart failure with reduced ejection fraction (HFrEF). Both are due to be completed in 2020.
In addition, the DELIVER trial is focused on 4,700 HFpEF patients randomized to dapagliflozin (Farxiga) or placebo, while Dapa-HF employs the SGLT2 inhibitor in a study of 4,500 patients with HFrEF. Dapa-HF will be completed by late 2019. DELIVER wraps up in mid-2021.
Again, remarkably, none of the participants in these trials has diabetes. All have symptomatic heart failure with elevated N-terminal pro b-type natriuretic peptide levels. The impetus for this ongoing round of studies was the impressive reduction in the risk of hospitalization for heart failure seen in the pivotal trials that earned the SGLT2 inhibitors empagliflozin, canagliflozin (Invokana), and dapagliflozin marketing approval for treatment of type 2 diabetes from the Food and Drug Administration.
Dr. Desai called attention to a new systematic review and meta-analysis of cardiovascular outcomes in randomized, placebo-controlled trials of SGLT2 inhibitors in more than 34,000 patients with type 2 diabetes. The conclusion: These drugs impressively reduced the risk of heart failure hospitalization by 32% in patients with a baseline history of heart failure and similarly by 29% in those with no such history. Also notable was the 45% reduction in the risk of progression of renal disease regardless of whether patients had atherosclerotic cardiovascular disease (Lancet. 2019 Jan 5;393[10166]:31-9).
Only one of the ongoing round of phase 3 trials of SGLT2 inhibitors in heart failure is being conducted in patients with comorbid type 2 diabetes: the 4,000-subject SOLOIST-WHF trial. This study features the investigational dual inhibitor of SGLT1 and 2, sotagliflozin, with a primary outcome of cardiovascular death or heart failure hospitalization. Results are expected in early 2021.
What the latest guidelines say
The 2018 American Diabetes Association/European Association for the Study of Diabetes joint consensus statement on management of hyperglycemia in type 2 diabetes reflects an appreciation of the cardiovascular benefits of the SGLT2 inhibitors as well as the injectable glucagon-like peptide-1 receptor (GLP-1) agonists, which have shown significant reductions in major adverse cardiovascular events in pivotal trials including LEADER, HARMONY, and REWIND, albeit without the impressive reduction in heart failure hospitalizations documented with the SGLT2 inhibitors.
The consensus statement emphasizes that aggressive lifestyle modification advice is step No. 1, with the first-line medication being metformin titrated to a target of 1,000 mg twice daily. For patients with clinical heart failure or chronic kidney disease and atherosclerotic cardiovascular heart disease, the next drug recommended is an SGLT2 inhibitor with proven cardiovascular benefit. A GLP-1 agonist is recommended as the first injectable medication, ahead of insulin.
Who will take the lead in this new treatment strategy?
Dr. Desai presented data showing that overall utilization of SGLT2 inhibitors and GLP-1 agonists is going up, but not as steeply as it should.
“Cardiologists need to take a more active role,” he declared.
“It’s increasingly clear that, if we’re interested in modifying cardiovascular outcomes, we need to take ownership of this problem, much as we’ve done for lipids and hypertension, because modulating cardiovascular risk is our job,” Dr. Desai asserted. “These drugs may have modest influence on glycemic control, but the primary goal with these agents is to influence cardiovascular outcomes – and if we leave that job to our colleagues, then it often is just a can that gets kicked down the road.”
As a practical matter in prescribing SGLT2 inhibitors and GLP-1 agonists, he emphasized the value of partnering with a primary care physician, endocrinologist, and/or pharmacist by creating pathways for accelerated referral for pharmacologic teaching and, in the case of GLP-1 agonists, injection-related instruction. Pharmacists are often particularly helpful in obtaining prior authorization and financial approval for these medications, and they are familiar with drug discounts and vouchers.
“A great way to jump start collaboration is to provide the patient with a prescription before leaving your office. I think often what we do is just suggest it to the patient, and then a year later they come back and nothing has changed,” the cardiologist said.
Dr. Desai reported serving as a paid consultant to more than half a dozen pharmaceutical or medical device companies.
SNOWMASS, COLO. – The oral sodium-glucose cotransporter-2 (SGLT2) inhibitors are the focus of a slew of ongoing phase 3 clinical trials in patients with symptomatic heart failure but no diabetes.
“We have a wide array of exciting opportunities to modify cardiovascular risk with agents that were initially developed for the therapy of diabetes. I think we’re increasingly moving to an age where these agents are actually cardiovascular drugs that happen to lower blood glucose, rather than the other way around, which is how they were initially conceived,” Akshay S. Desai, MD, observed at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
These are each multi-thousand-patient trials, variously due to be completed in 2019-2021. Of note, several of them are restricted to nondiabetic patients with heart failure with preserved ejection fraction (HFpEF), a common, serious, understudied, extremely high-cost disease sorely in need of effective pharmacotherapies, added Dr. Desai, director of the cardiomyopathy and heart failure program at Brigham and Women’s Hospital and a cardiologist at Harvard Medical School, Boston.
All of these placebo-controlled trials have as their composite primary endpoint cardiovascular death and heart failure hospitalization.
EMPEROR-Preserved has randomized 4,126 patients with HFpEF to empagliflozin (Jardiance) or placebo, while EMPEROR-Reduced involves 2,850 patients with heart failure with reduced ejection fraction (HFrEF). Both are due to be completed in 2020.
In addition, the DELIVER trial is focused on 4,700 HFpEF patients randomized to dapagliflozin (Farxiga) or placebo, while Dapa-HF employs the SGLT2 inhibitor in a study of 4,500 patients with HFrEF. Dapa-HF will be completed by late 2019. DELIVER wraps up in mid-2021.
Again, remarkably, none of the participants in these trials has diabetes. All have symptomatic heart failure with elevated N-terminal pro b-type natriuretic peptide levels. The impetus for this ongoing round of studies was the impressive reduction in the risk of hospitalization for heart failure seen in the pivotal trials that earned the SGLT2 inhibitors empagliflozin, canagliflozin (Invokana), and dapagliflozin marketing approval for treatment of type 2 diabetes from the Food and Drug Administration.
Dr. Desai called attention to a new systematic review and meta-analysis of cardiovascular outcomes in randomized, placebo-controlled trials of SGLT2 inhibitors in more than 34,000 patients with type 2 diabetes. The conclusion: These drugs impressively reduced the risk of heart failure hospitalization by 32% in patients with a baseline history of heart failure and similarly by 29% in those with no such history. Also notable was the 45% reduction in the risk of progression of renal disease regardless of whether patients had atherosclerotic cardiovascular disease (Lancet. 2019 Jan 5;393[10166]:31-9).
Only one of the ongoing round of phase 3 trials of SGLT2 inhibitors in heart failure is being conducted in patients with comorbid type 2 diabetes: the 4,000-subject SOLOIST-WHF trial. This study features the investigational dual inhibitor of SGLT1 and 2, sotagliflozin, with a primary outcome of cardiovascular death or heart failure hospitalization. Results are expected in early 2021.
What the latest guidelines say
The 2018 American Diabetes Association/European Association for the Study of Diabetes joint consensus statement on management of hyperglycemia in type 2 diabetes reflects an appreciation of the cardiovascular benefits of the SGLT2 inhibitors as well as the injectable glucagon-like peptide-1 receptor (GLP-1) agonists, which have shown significant reductions in major adverse cardiovascular events in pivotal trials including LEADER, HARMONY, and REWIND, albeit without the impressive reduction in heart failure hospitalizations documented with the SGLT2 inhibitors.
The consensus statement emphasizes that aggressive lifestyle modification advice is step No. 1, with the first-line medication being metformin titrated to a target of 1,000 mg twice daily. For patients with clinical heart failure or chronic kidney disease and atherosclerotic cardiovascular heart disease, the next drug recommended is an SGLT2 inhibitor with proven cardiovascular benefit. A GLP-1 agonist is recommended as the first injectable medication, ahead of insulin.
Who will take the lead in this new treatment strategy?
Dr. Desai presented data showing that overall utilization of SGLT2 inhibitors and GLP-1 agonists is going up, but not as steeply as it should.
“Cardiologists need to take a more active role,” he declared.
“It’s increasingly clear that, if we’re interested in modifying cardiovascular outcomes, we need to take ownership of this problem, much as we’ve done for lipids and hypertension, because modulating cardiovascular risk is our job,” Dr. Desai asserted. “These drugs may have modest influence on glycemic control, but the primary goal with these agents is to influence cardiovascular outcomes – and if we leave that job to our colleagues, then it often is just a can that gets kicked down the road.”
As a practical matter in prescribing SGLT2 inhibitors and GLP-1 agonists, he emphasized the value of partnering with a primary care physician, endocrinologist, and/or pharmacist by creating pathways for accelerated referral for pharmacologic teaching and, in the case of GLP-1 agonists, injection-related instruction. Pharmacists are often particularly helpful in obtaining prior authorization and financial approval for these medications, and they are familiar with drug discounts and vouchers.
“A great way to jump start collaboration is to provide the patient with a prescription before leaving your office. I think often what we do is just suggest it to the patient, and then a year later they come back and nothing has changed,” the cardiologist said.
Dr. Desai reported serving as a paid consultant to more than half a dozen pharmaceutical or medical device companies.
SNOWMASS, COLO. – The oral sodium-glucose cotransporter-2 (SGLT2) inhibitors are the focus of a slew of ongoing phase 3 clinical trials in patients with symptomatic heart failure but no diabetes.
“We have a wide array of exciting opportunities to modify cardiovascular risk with agents that were initially developed for the therapy of diabetes. I think we’re increasingly moving to an age where these agents are actually cardiovascular drugs that happen to lower blood glucose, rather than the other way around, which is how they were initially conceived,” Akshay S. Desai, MD, observed at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
These are each multi-thousand-patient trials, variously due to be completed in 2019-2021. Of note, several of them are restricted to nondiabetic patients with heart failure with preserved ejection fraction (HFpEF), a common, serious, understudied, extremely high-cost disease sorely in need of effective pharmacotherapies, added Dr. Desai, director of the cardiomyopathy and heart failure program at Brigham and Women’s Hospital and a cardiologist at Harvard Medical School, Boston.
All of these placebo-controlled trials have as their composite primary endpoint cardiovascular death and heart failure hospitalization.
EMPEROR-Preserved has randomized 4,126 patients with HFpEF to empagliflozin (Jardiance) or placebo, while EMPEROR-Reduced involves 2,850 patients with heart failure with reduced ejection fraction (HFrEF). Both are due to be completed in 2020.
In addition, the DELIVER trial is focused on 4,700 HFpEF patients randomized to dapagliflozin (Farxiga) or placebo, while Dapa-HF employs the SGLT2 inhibitor in a study of 4,500 patients with HFrEF. Dapa-HF will be completed by late 2019. DELIVER wraps up in mid-2021.
Again, remarkably, none of the participants in these trials has diabetes. All have symptomatic heart failure with elevated N-terminal pro b-type natriuretic peptide levels. The impetus for this ongoing round of studies was the impressive reduction in the risk of hospitalization for heart failure seen in the pivotal trials that earned the SGLT2 inhibitors empagliflozin, canagliflozin (Invokana), and dapagliflozin marketing approval for treatment of type 2 diabetes from the Food and Drug Administration.
Dr. Desai called attention to a new systematic review and meta-analysis of cardiovascular outcomes in randomized, placebo-controlled trials of SGLT2 inhibitors in more than 34,000 patients with type 2 diabetes. The conclusion: These drugs impressively reduced the risk of heart failure hospitalization by 32% in patients with a baseline history of heart failure and similarly by 29% in those with no such history. Also notable was the 45% reduction in the risk of progression of renal disease regardless of whether patients had atherosclerotic cardiovascular disease (Lancet. 2019 Jan 5;393[10166]:31-9).
Only one of the ongoing round of phase 3 trials of SGLT2 inhibitors in heart failure is being conducted in patients with comorbid type 2 diabetes: the 4,000-subject SOLOIST-WHF trial. This study features the investigational dual inhibitor of SGLT1 and 2, sotagliflozin, with a primary outcome of cardiovascular death or heart failure hospitalization. Results are expected in early 2021.
What the latest guidelines say
The 2018 American Diabetes Association/European Association for the Study of Diabetes joint consensus statement on management of hyperglycemia in type 2 diabetes reflects an appreciation of the cardiovascular benefits of the SGLT2 inhibitors as well as the injectable glucagon-like peptide-1 receptor (GLP-1) agonists, which have shown significant reductions in major adverse cardiovascular events in pivotal trials including LEADER, HARMONY, and REWIND, albeit without the impressive reduction in heart failure hospitalizations documented with the SGLT2 inhibitors.
The consensus statement emphasizes that aggressive lifestyle modification advice is step No. 1, with the first-line medication being metformin titrated to a target of 1,000 mg twice daily. For patients with clinical heart failure or chronic kidney disease and atherosclerotic cardiovascular heart disease, the next drug recommended is an SGLT2 inhibitor with proven cardiovascular benefit. A GLP-1 agonist is recommended as the first injectable medication, ahead of insulin.
Who will take the lead in this new treatment strategy?
Dr. Desai presented data showing that overall utilization of SGLT2 inhibitors and GLP-1 agonists is going up, but not as steeply as it should.
“Cardiologists need to take a more active role,” he declared.
“It’s increasingly clear that, if we’re interested in modifying cardiovascular outcomes, we need to take ownership of this problem, much as we’ve done for lipids and hypertension, because modulating cardiovascular risk is our job,” Dr. Desai asserted. “These drugs may have modest influence on glycemic control, but the primary goal with these agents is to influence cardiovascular outcomes – and if we leave that job to our colleagues, then it often is just a can that gets kicked down the road.”
As a practical matter in prescribing SGLT2 inhibitors and GLP-1 agonists, he emphasized the value of partnering with a primary care physician, endocrinologist, and/or pharmacist by creating pathways for accelerated referral for pharmacologic teaching and, in the case of GLP-1 agonists, injection-related instruction. Pharmacists are often particularly helpful in obtaining prior authorization and financial approval for these medications, and they are familiar with drug discounts and vouchers.
“A great way to jump start collaboration is to provide the patient with a prescription before leaving your office. I think often what we do is just suggest it to the patient, and then a year later they come back and nothing has changed,” the cardiologist said.
Dr. Desai reported serving as a paid consultant to more than half a dozen pharmaceutical or medical device companies.
EXPERT ANALYSIS FROM ACC SNOWMASS 2019