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CHICAGO – When the first results from a large trial that showed profound and unexpected benefits for preventing heart failure hospitalizations associated with use of the antihyperglycemic sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin came out – a little over 3 years ago – the general reaction from clinicians was some variant of “Could this be real?”
Since then, as results from some five other large, international trials have come out showing both similar benefits from two other drugs in the same SGLT2 inhibitor class, canagliflozin and dapagliflozin, as well as results showing clear cardiovascular disease benefits from three drugs in a second class of antihyperglycemics, the glucagonlike peptide–1 receptor agonists (GLP-1 RAs), the general consensus among cardiologists became: “The cardiovascular and renal benefits are real. How can we now best use these drugs to help patients?”
This change increasingly forces cardiologists, as well as the primary care physicians who often manage patients with type 2 diabetes mellitus, to become more comfortable prescribing these two classes of antihyperglycemic drugs. During a talk at the American Heart Association scientific sessions, Eugene Braunwald, MD, arguably the top thought leader in cardiology, coined a new name for the medical subspecialty that he foresees navigating this overlap between diabetes care and cardiovascular disease prevention: diabetocardiology (although a more euphonic alternative might be cardiodiabetology, while the more comprehensive name could be cardionephrodiabetology).
“I was certainly surprised” by the first report in 2015 from the EMPA-REG OUTCOME trial (N Engl J Med. 2015 Nov 26;373[22]:2117-28), said Dr. Braunwald, who is professor of medicine at Harvard Medical School in Boston. A lot of his colleagues were surprised and said, “It’s just one trial.”
“Now we have three trials,” with the addition of the CANVAS trial for canagliflozin (N Engl J Med. 2017 Aug 17;377[7]:644-57) and the DECLARE-TIMI 58 trial (N Engl J Med. 2018 Nov 10. doi:10.1056/NEJMoa1812389) for dapagliflozin reported at the AHA meeting in November.
“We are in the midst of two pandemics: heart failure and type 2 diabetes. As cardiologists, we have to learn how to deal with this,” said Dr. Braunwald, and the evidence now clearly shows that these drugs can help with that.
As another speaker at the meeting, Javed Butler, MD, a heart failure specialist, observed in a separate talk at the meeting, “Heart failure is one of the most common, if not the most common complication, of patients with diabetes.” This tight link between heart failure and diabetes helps make cardiovascular mortality “the number one cause of death” in patients with diabetes, said Dr. Butler, professor and chairman of medicine at the University of Mississippi in Jackson.
“Thanks to the cardiovascular outcome trials, we now have a much broader and deeper appreciation of heart failure and renal disease as integral components of the cardiovascular-renal spectrum in people with diabetes,” said Subodh Verma, MD, a professor at the University of Toronto and cardiac surgeon at St. Michael’s Hospital in Toronto. Dr. Braunwald spelled out in his talk some of the interrelationships of diabetes, heart failure, and renal dysfunction that together produce a downward-spiraling vicious circle for patients, a pathophysiological process that clinicians can now short-circuit by treatment with a SGLT2 inhibitor.
Cardiovascular outcome trials show the way
In the context of antihyperglycemic drugs, the “cardiovascular outcome trials” refers to a series of large trials mandated by the Food and Drug Administration in 2008 to assess the cardiovascular disease effects of new agents coming onto the U.S. market to treat type 2 diabetes mellitus (T2DM). By the time Dr. Verma spoke at the AHA meeting, he could cite reported results from 12 of these trials: 5 different drugs in the GLP-1 RA class, 4 drugs in the dipeptidyl peptidase-4 (DPP-4) inhibitor class, and 3 drugs from the SGLT2 inhibitor class. Dr. Verma summed what the findings have shown.
The four tested DDP-4 inhibitors (alogliptin, linagliptin, saxagliptin, and sitagliptin) consistently showed neutrality for the primary outcome of major adverse cardiovascular disease events (MACE), constituted by cardiovascular disease death, MI, or stroke.
The five tested GLP-1 RAs (albiglutide, exenatide, liraglutide, lixisenatide, and semaglutide) showed a mixed pattern of MACE results that seemed to be linked with the subclass the drug fell into. The two exedin-4–based drugs, exenatide and lixisenatide, each showed a statistically neutral effect for MACE, as well as collectively in a combined analysis. In contrast, three human GLP-1–based drugs, albiglutide, liraglutide, and semaglutide, each showed a consistent, statistically-significant MACE reduction in their respective outcome trials, and collectively they showed a highly significant 18% reduction in MACE, compared with placebo, Dr. Verma said. Further, recent analysis by Dr. Verma that used data from liraglutide treatment in the LEADER trial showed the MACE benefit occurred only among enrolled patients treated with liraglutide who had established atherosclerotic cardiovascular disease (ASCVD). Patients enrolled in the trial with only multiple risk factors (in addition to having T2DM) but without established ASCVD showed no significant benefit from liraglutide treatment for the MACE endpoint, compared with control patients.
Recently a press-release announcement of results from a sixth GLP-1 RA, dulaglutide, in the REWIND trial of MACE outcomes suggested that a drug in this class could have broader effect. The majority, 69%, of the 9,901 patients with T2DM enrolled in REWIND had risk factors but not established ASCVD at enrollment. A Nov. 5, 2018, statement from the company developing this drug, Lilly, reported that the study overall produced a statistically significant reduction in MACE, although it provided no additional details. As the released noted, this made REWIND the first trial to show a MACE benefit from a drug in the GLP-1 RA class in patients without established ASCVD.
The MACE outcome results from the three SGLT2 inhibitor trials showed a similar pattern as liraglutide: In patients with established ASCVD, the drugs individually each produced a MACE reduction, although dapagliflozin just missed having a statistically significant reduction. Collectively, the three drugs showed a statistically significant, 14% relative risk reduction for MACE, compared with control patients. But among patients with multiple risk factors only, but without established ASCVD, included in two of the three trials (CANVAS and DECLARE-TIMI 58), the results showed both individually and collectively a neutral MACE effect.
But unlike the other antihyperglycemic drugs tested in the cardiovascular outcome trials, the SGLT2 inhibitors have shown two additional, highly important secondary outcomes: a consistent reduction in hospitalization for heart failure and a consistent reduction in renal-disease progression.
A meta-analysis of the three SGLT2 inhibitor trials published coincident with the release of the DECLARE-TIMI 58 results showed that, for the outcome of either cardiovascular death or hospitalization for heart failure, the SGLT2 inhibitors collectively showed a significant 29% relative decrease in this incidence among patients with a history of heart failure, and a significant 21% relative decrease among patients without history of heart failure (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32590-X). Among the subset of patients with established ASCVD, treatment with a SGLT2 inhibitor across all three trials showed a significant 16% relative risk reduction, and in the subset with multiple risk factors but no established ASCVD, the two SGLT2 inhibitors collectively produced a 16% relative cut in cardiovascular death or heart failure hospitalization with a P value of .06. Finally, the Lancet meta-analysis showed that, for a combined endpoint that reflected renal worsening, the SGLT2 inhibitors showed a significant relative reduction of about 45% in both the subgroup of patients with established ASCVD and in the subgroup of those with just risk factors.
“This is a big step forward for patients with multiple risk factors and diabetes but without ASCVD, that both renal disease and hospitalization for heart failure are sensitive” to the SGLT2 inhibitors, Dr. Verma noted. “We see renal protection and reduction of heart failure hospitalization across both primary and secondary prevention patients, with no need to distinguish them based on ASCVD.” In contrast, he noted, the MACE benefit from the SGLT2 inhibitors seems limited to patients with ASCVD. The day before making this point in a talk during the meeting, Dr. Verma had published the same message in a commentary (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32824-1).
Although the “nomenclature of primary versus secondary prevention is appropriate for atherosclerotic outcomes, it is likely to be inappropriate for a person with type 2 diabetes who is at risk of hospitalization for heart failure and renal disease,” Dr. Verma wrote with his associates in the commentary.
What it means for clinicians
The upshot of all of these cardiovascular outcome trial results that came out over the past 3 years has been a new appreciation of how antihyperglycemic drugs can have cardiovascular and renal benefits that transcend their effects on glycemia. The evidence has put the SGLT2 inhibitors and GLP-1 RAs on track to challenge, and potentially displace, metformin as the top drug to prescribe for patients with T2DM.
Clinicians should realize that they should prescribe SGLT2 inhibitors and selected GLP-1 RAs “as early as metformin in patients with established ASCVD,” said Dr. Verma. “For patients with recalcitrant atherosclerotic disease and a history of MI and ischemia, I’d primarily treat with a GLP-1 RA. In a patient with left ventricular dysfunction or evidence of heart failure, I’d use an SGLT2 inhibitor. But it’s not a fight between these two. You could treat a patients with type 2 diabetes with both classes,” although the practicality of this approach is limited by the high cost of these drugs.
The SGLT2 inhibitors “should now be considered as first-line therapy after metformin in most people with type 2 diabetes, irrespective of whether or not they have established atherosclerotic vascular disease, chronic kidney disease, or heart failure,” he and his associates wrote in their recent commentary.
“What I struggle with the most is how we prioritize and individualize secondary-prevention therapies based on risk for ischemia and heart failure. Some therapies [the SGLT2 inhibitors] are predominantly for heart failure prevention, and some [the GLP-1 RAs] are primarily for ischemia. How do we choose when a patient cannot afford to take both? Does a combination of a SGLT2 inhibitor and a GLP-1 RA offer the greatest CVD benefit? We need to test this in a trial. And will metformin be displaced as first-line treatment?” Dr. Verma asked.
“The day will probably come when, for maximal protection, you treat with both classes. But right now we’re forced to choose because of the cost,” said John McMurray, MD, professor of cardiology at the University of Glasgow, in a talk during the meeting.
As to specifically which SGLT2 inhibitor to prescribe, “they all look pretty much the same” in the newly published meta-analysis, Dr. McMurray said, although he noted that safety differences among agents in the class remain possible.
“For patients similar to those studied in the three SGLT2 inhibitor trials, clinicians should use one of these drugs to reduce the risk for incident heart failure, irrespective of their effect on MACE,” said Dr. Butler. Reducing the risk for incident heart failure and of progressive renal dysfunction are two new goals for antihyperglycemic therapy that now overlay the long-standing goals of controlling glycemia and reducing cardiovascular disease risk and the more recent goals of cutting cardiovascular disease mortality and cutting the risk for a MACE event.
A current limitation for practice is that the none of the three drug companies that market the tested SGLT2 inhibitor drugs has sought regulatory approval for an indication of reducing the risk for heart failure hospitalization. Despite that, “these drugs should be used for renal protection and reducing heart failure hospitalizations,” Dr. Butler said. “We need to start thinking about this and not get lost thinking about only their MACE effect because, when you focus on MACE, there is a competition between the SGLT2 inhibitors and the GLP-1 RA. If we think of GLP-1 RAs as drugs to prevent MACE, and SGLT2 inhibitors as drugs that primarily prevent heart failure and renal dysfunction, then there is no competition. Perhaps combined treatment is where we need to go,” he said in an interview.
But the enthusiasm that experts like Dr. Butler, Dr. McMurray, and Dr. Verma have for wider use of both classes of drugs in appropriate patients is not necessarily matched right now among many community physicians. Cardiologist David J. Becker, MD, is an example of the clinicians who appreciate the growing evidence that supports wider use of these antihyperglycemic drugs but remain uneasy about applying this evidence in their practice.
Dr. Becker, associate director of the Preventive and Integrative Heart Health Program of the Temple Heart and Vascular Institute in Philadelphia, writes a column for the Philadelphia Inquirer on medical care. In a December 2018 piece, he said “like most cardiologists, I ‘don’t do diabetes’ – because it’s not my expertise. The new drugs, however, mean I need to learn more” about treating these patients. “The problem: There are so many of these medications that they present a bewildering choice for patients and doctors.”
Dr. Becker cited several barriers he sees for himself and his nonendocrinologist colleagues to prescribe these drugs – and for patients to take them:
- High cost, with prices that run close to $20/day for each medication.
- A thicket of names and choices that “lead to confusion and paralysis,” which has been exacerbated by “advertising wars” among competing drug companies.
- Cardiologists and primary care physicians usually defer to endocrinologists to prescribe these drugs, but most patients with T2DM aren’t seen by endocrinologists. The result: “Few doctors prescribe them.”
The cardiovascular disease benefits of these drugs have not been adequately promoted. Until that changes, “cardiologists like me will not realize their importance,” Dr. Becker concluded.
While christening the new diabetocardiology subspecialty, Dr. Braunwald placed the onus for managing this emerging facet of diabetes largely outside the scope of endocrinology.
“We can’t call in a consultant every time we have a patient with diabetes; it would bankrupt the system,” he said. Training of cardiologists now needs to include several months of treating patients with diabetes, Dr. Braunwald advised, just like 30 or so years ago when cardiologists like himself had to become more familiar with blood clotting to better manage thrombotic disease.
Dr. Braunwald has been a consultant to Cardurion, Myokardia, and Sanofi; an advisor to Endcardia; and has received research funding from AstraZeneca, Daiishi Sankyo, and Novartis. Dr. Butler has been a consultant or advisor to AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Janssen, Merck, Novartis, Novo Nordisk, and Sanofi. Dr. Verma has received honoraria and research funding from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, NovoNordisk, Sanofi, and Valeant. Dr. McMurray has received research funding from 12 companies. Dr. Becker had no disclosures.
CHICAGO – When the first results from a large trial that showed profound and unexpected benefits for preventing heart failure hospitalizations associated with use of the antihyperglycemic sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin came out – a little over 3 years ago – the general reaction from clinicians was some variant of “Could this be real?”
Since then, as results from some five other large, international trials have come out showing both similar benefits from two other drugs in the same SGLT2 inhibitor class, canagliflozin and dapagliflozin, as well as results showing clear cardiovascular disease benefits from three drugs in a second class of antihyperglycemics, the glucagonlike peptide–1 receptor agonists (GLP-1 RAs), the general consensus among cardiologists became: “The cardiovascular and renal benefits are real. How can we now best use these drugs to help patients?”
This change increasingly forces cardiologists, as well as the primary care physicians who often manage patients with type 2 diabetes mellitus, to become more comfortable prescribing these two classes of antihyperglycemic drugs. During a talk at the American Heart Association scientific sessions, Eugene Braunwald, MD, arguably the top thought leader in cardiology, coined a new name for the medical subspecialty that he foresees navigating this overlap between diabetes care and cardiovascular disease prevention: diabetocardiology (although a more euphonic alternative might be cardiodiabetology, while the more comprehensive name could be cardionephrodiabetology).
“I was certainly surprised” by the first report in 2015 from the EMPA-REG OUTCOME trial (N Engl J Med. 2015 Nov 26;373[22]:2117-28), said Dr. Braunwald, who is professor of medicine at Harvard Medical School in Boston. A lot of his colleagues were surprised and said, “It’s just one trial.”
“Now we have three trials,” with the addition of the CANVAS trial for canagliflozin (N Engl J Med. 2017 Aug 17;377[7]:644-57) and the DECLARE-TIMI 58 trial (N Engl J Med. 2018 Nov 10. doi:10.1056/NEJMoa1812389) for dapagliflozin reported at the AHA meeting in November.
“We are in the midst of two pandemics: heart failure and type 2 diabetes. As cardiologists, we have to learn how to deal with this,” said Dr. Braunwald, and the evidence now clearly shows that these drugs can help with that.
As another speaker at the meeting, Javed Butler, MD, a heart failure specialist, observed in a separate talk at the meeting, “Heart failure is one of the most common, if not the most common complication, of patients with diabetes.” This tight link between heart failure and diabetes helps make cardiovascular mortality “the number one cause of death” in patients with diabetes, said Dr. Butler, professor and chairman of medicine at the University of Mississippi in Jackson.
“Thanks to the cardiovascular outcome trials, we now have a much broader and deeper appreciation of heart failure and renal disease as integral components of the cardiovascular-renal spectrum in people with diabetes,” said Subodh Verma, MD, a professor at the University of Toronto and cardiac surgeon at St. Michael’s Hospital in Toronto. Dr. Braunwald spelled out in his talk some of the interrelationships of diabetes, heart failure, and renal dysfunction that together produce a downward-spiraling vicious circle for patients, a pathophysiological process that clinicians can now short-circuit by treatment with a SGLT2 inhibitor.
Cardiovascular outcome trials show the way
In the context of antihyperglycemic drugs, the “cardiovascular outcome trials” refers to a series of large trials mandated by the Food and Drug Administration in 2008 to assess the cardiovascular disease effects of new agents coming onto the U.S. market to treat type 2 diabetes mellitus (T2DM). By the time Dr. Verma spoke at the AHA meeting, he could cite reported results from 12 of these trials: 5 different drugs in the GLP-1 RA class, 4 drugs in the dipeptidyl peptidase-4 (DPP-4) inhibitor class, and 3 drugs from the SGLT2 inhibitor class. Dr. Verma summed what the findings have shown.
The four tested DDP-4 inhibitors (alogliptin, linagliptin, saxagliptin, and sitagliptin) consistently showed neutrality for the primary outcome of major adverse cardiovascular disease events (MACE), constituted by cardiovascular disease death, MI, or stroke.
The five tested GLP-1 RAs (albiglutide, exenatide, liraglutide, lixisenatide, and semaglutide) showed a mixed pattern of MACE results that seemed to be linked with the subclass the drug fell into. The two exedin-4–based drugs, exenatide and lixisenatide, each showed a statistically neutral effect for MACE, as well as collectively in a combined analysis. In contrast, three human GLP-1–based drugs, albiglutide, liraglutide, and semaglutide, each showed a consistent, statistically-significant MACE reduction in their respective outcome trials, and collectively they showed a highly significant 18% reduction in MACE, compared with placebo, Dr. Verma said. Further, recent analysis by Dr. Verma that used data from liraglutide treatment in the LEADER trial showed the MACE benefit occurred only among enrolled patients treated with liraglutide who had established atherosclerotic cardiovascular disease (ASCVD). Patients enrolled in the trial with only multiple risk factors (in addition to having T2DM) but without established ASCVD showed no significant benefit from liraglutide treatment for the MACE endpoint, compared with control patients.
Recently a press-release announcement of results from a sixth GLP-1 RA, dulaglutide, in the REWIND trial of MACE outcomes suggested that a drug in this class could have broader effect. The majority, 69%, of the 9,901 patients with T2DM enrolled in REWIND had risk factors but not established ASCVD at enrollment. A Nov. 5, 2018, statement from the company developing this drug, Lilly, reported that the study overall produced a statistically significant reduction in MACE, although it provided no additional details. As the released noted, this made REWIND the first trial to show a MACE benefit from a drug in the GLP-1 RA class in patients without established ASCVD.
The MACE outcome results from the three SGLT2 inhibitor trials showed a similar pattern as liraglutide: In patients with established ASCVD, the drugs individually each produced a MACE reduction, although dapagliflozin just missed having a statistically significant reduction. Collectively, the three drugs showed a statistically significant, 14% relative risk reduction for MACE, compared with control patients. But among patients with multiple risk factors only, but without established ASCVD, included in two of the three trials (CANVAS and DECLARE-TIMI 58), the results showed both individually and collectively a neutral MACE effect.
But unlike the other antihyperglycemic drugs tested in the cardiovascular outcome trials, the SGLT2 inhibitors have shown two additional, highly important secondary outcomes: a consistent reduction in hospitalization for heart failure and a consistent reduction in renal-disease progression.
A meta-analysis of the three SGLT2 inhibitor trials published coincident with the release of the DECLARE-TIMI 58 results showed that, for the outcome of either cardiovascular death or hospitalization for heart failure, the SGLT2 inhibitors collectively showed a significant 29% relative decrease in this incidence among patients with a history of heart failure, and a significant 21% relative decrease among patients without history of heart failure (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32590-X). Among the subset of patients with established ASCVD, treatment with a SGLT2 inhibitor across all three trials showed a significant 16% relative risk reduction, and in the subset with multiple risk factors but no established ASCVD, the two SGLT2 inhibitors collectively produced a 16% relative cut in cardiovascular death or heart failure hospitalization with a P value of .06. Finally, the Lancet meta-analysis showed that, for a combined endpoint that reflected renal worsening, the SGLT2 inhibitors showed a significant relative reduction of about 45% in both the subgroup of patients with established ASCVD and in the subgroup of those with just risk factors.
“This is a big step forward for patients with multiple risk factors and diabetes but without ASCVD, that both renal disease and hospitalization for heart failure are sensitive” to the SGLT2 inhibitors, Dr. Verma noted. “We see renal protection and reduction of heart failure hospitalization across both primary and secondary prevention patients, with no need to distinguish them based on ASCVD.” In contrast, he noted, the MACE benefit from the SGLT2 inhibitors seems limited to patients with ASCVD. The day before making this point in a talk during the meeting, Dr. Verma had published the same message in a commentary (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32824-1).
Although the “nomenclature of primary versus secondary prevention is appropriate for atherosclerotic outcomes, it is likely to be inappropriate for a person with type 2 diabetes who is at risk of hospitalization for heart failure and renal disease,” Dr. Verma wrote with his associates in the commentary.
What it means for clinicians
The upshot of all of these cardiovascular outcome trial results that came out over the past 3 years has been a new appreciation of how antihyperglycemic drugs can have cardiovascular and renal benefits that transcend their effects on glycemia. The evidence has put the SGLT2 inhibitors and GLP-1 RAs on track to challenge, and potentially displace, metformin as the top drug to prescribe for patients with T2DM.
Clinicians should realize that they should prescribe SGLT2 inhibitors and selected GLP-1 RAs “as early as metformin in patients with established ASCVD,” said Dr. Verma. “For patients with recalcitrant atherosclerotic disease and a history of MI and ischemia, I’d primarily treat with a GLP-1 RA. In a patient with left ventricular dysfunction or evidence of heart failure, I’d use an SGLT2 inhibitor. But it’s not a fight between these two. You could treat a patients with type 2 diabetes with both classes,” although the practicality of this approach is limited by the high cost of these drugs.
The SGLT2 inhibitors “should now be considered as first-line therapy after metformin in most people with type 2 diabetes, irrespective of whether or not they have established atherosclerotic vascular disease, chronic kidney disease, or heart failure,” he and his associates wrote in their recent commentary.
“What I struggle with the most is how we prioritize and individualize secondary-prevention therapies based on risk for ischemia and heart failure. Some therapies [the SGLT2 inhibitors] are predominantly for heart failure prevention, and some [the GLP-1 RAs] are primarily for ischemia. How do we choose when a patient cannot afford to take both? Does a combination of a SGLT2 inhibitor and a GLP-1 RA offer the greatest CVD benefit? We need to test this in a trial. And will metformin be displaced as first-line treatment?” Dr. Verma asked.
“The day will probably come when, for maximal protection, you treat with both classes. But right now we’re forced to choose because of the cost,” said John McMurray, MD, professor of cardiology at the University of Glasgow, in a talk during the meeting.
As to specifically which SGLT2 inhibitor to prescribe, “they all look pretty much the same” in the newly published meta-analysis, Dr. McMurray said, although he noted that safety differences among agents in the class remain possible.
“For patients similar to those studied in the three SGLT2 inhibitor trials, clinicians should use one of these drugs to reduce the risk for incident heart failure, irrespective of their effect on MACE,” said Dr. Butler. Reducing the risk for incident heart failure and of progressive renal dysfunction are two new goals for antihyperglycemic therapy that now overlay the long-standing goals of controlling glycemia and reducing cardiovascular disease risk and the more recent goals of cutting cardiovascular disease mortality and cutting the risk for a MACE event.
A current limitation for practice is that the none of the three drug companies that market the tested SGLT2 inhibitor drugs has sought regulatory approval for an indication of reducing the risk for heart failure hospitalization. Despite that, “these drugs should be used for renal protection and reducing heart failure hospitalizations,” Dr. Butler said. “We need to start thinking about this and not get lost thinking about only their MACE effect because, when you focus on MACE, there is a competition between the SGLT2 inhibitors and the GLP-1 RA. If we think of GLP-1 RAs as drugs to prevent MACE, and SGLT2 inhibitors as drugs that primarily prevent heart failure and renal dysfunction, then there is no competition. Perhaps combined treatment is where we need to go,” he said in an interview.
But the enthusiasm that experts like Dr. Butler, Dr. McMurray, and Dr. Verma have for wider use of both classes of drugs in appropriate patients is not necessarily matched right now among many community physicians. Cardiologist David J. Becker, MD, is an example of the clinicians who appreciate the growing evidence that supports wider use of these antihyperglycemic drugs but remain uneasy about applying this evidence in their practice.
Dr. Becker, associate director of the Preventive and Integrative Heart Health Program of the Temple Heart and Vascular Institute in Philadelphia, writes a column for the Philadelphia Inquirer on medical care. In a December 2018 piece, he said “like most cardiologists, I ‘don’t do diabetes’ – because it’s not my expertise. The new drugs, however, mean I need to learn more” about treating these patients. “The problem: There are so many of these medications that they present a bewildering choice for patients and doctors.”
Dr. Becker cited several barriers he sees for himself and his nonendocrinologist colleagues to prescribe these drugs – and for patients to take them:
- High cost, with prices that run close to $20/day for each medication.
- A thicket of names and choices that “lead to confusion and paralysis,” which has been exacerbated by “advertising wars” among competing drug companies.
- Cardiologists and primary care physicians usually defer to endocrinologists to prescribe these drugs, but most patients with T2DM aren’t seen by endocrinologists. The result: “Few doctors prescribe them.”
The cardiovascular disease benefits of these drugs have not been adequately promoted. Until that changes, “cardiologists like me will not realize their importance,” Dr. Becker concluded.
While christening the new diabetocardiology subspecialty, Dr. Braunwald placed the onus for managing this emerging facet of diabetes largely outside the scope of endocrinology.
“We can’t call in a consultant every time we have a patient with diabetes; it would bankrupt the system,” he said. Training of cardiologists now needs to include several months of treating patients with diabetes, Dr. Braunwald advised, just like 30 or so years ago when cardiologists like himself had to become more familiar with blood clotting to better manage thrombotic disease.
Dr. Braunwald has been a consultant to Cardurion, Myokardia, and Sanofi; an advisor to Endcardia; and has received research funding from AstraZeneca, Daiishi Sankyo, and Novartis. Dr. Butler has been a consultant or advisor to AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Janssen, Merck, Novartis, Novo Nordisk, and Sanofi. Dr. Verma has received honoraria and research funding from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, NovoNordisk, Sanofi, and Valeant. Dr. McMurray has received research funding from 12 companies. Dr. Becker had no disclosures.
CHICAGO – When the first results from a large trial that showed profound and unexpected benefits for preventing heart failure hospitalizations associated with use of the antihyperglycemic sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin came out – a little over 3 years ago – the general reaction from clinicians was some variant of “Could this be real?”
Since then, as results from some five other large, international trials have come out showing both similar benefits from two other drugs in the same SGLT2 inhibitor class, canagliflozin and dapagliflozin, as well as results showing clear cardiovascular disease benefits from three drugs in a second class of antihyperglycemics, the glucagonlike peptide–1 receptor agonists (GLP-1 RAs), the general consensus among cardiologists became: “The cardiovascular and renal benefits are real. How can we now best use these drugs to help patients?”
This change increasingly forces cardiologists, as well as the primary care physicians who often manage patients with type 2 diabetes mellitus, to become more comfortable prescribing these two classes of antihyperglycemic drugs. During a talk at the American Heart Association scientific sessions, Eugene Braunwald, MD, arguably the top thought leader in cardiology, coined a new name for the medical subspecialty that he foresees navigating this overlap between diabetes care and cardiovascular disease prevention: diabetocardiology (although a more euphonic alternative might be cardiodiabetology, while the more comprehensive name could be cardionephrodiabetology).
“I was certainly surprised” by the first report in 2015 from the EMPA-REG OUTCOME trial (N Engl J Med. 2015 Nov 26;373[22]:2117-28), said Dr. Braunwald, who is professor of medicine at Harvard Medical School in Boston. A lot of his colleagues were surprised and said, “It’s just one trial.”
“Now we have three trials,” with the addition of the CANVAS trial for canagliflozin (N Engl J Med. 2017 Aug 17;377[7]:644-57) and the DECLARE-TIMI 58 trial (N Engl J Med. 2018 Nov 10. doi:10.1056/NEJMoa1812389) for dapagliflozin reported at the AHA meeting in November.
“We are in the midst of two pandemics: heart failure and type 2 diabetes. As cardiologists, we have to learn how to deal with this,” said Dr. Braunwald, and the evidence now clearly shows that these drugs can help with that.
As another speaker at the meeting, Javed Butler, MD, a heart failure specialist, observed in a separate talk at the meeting, “Heart failure is one of the most common, if not the most common complication, of patients with diabetes.” This tight link between heart failure and diabetes helps make cardiovascular mortality “the number one cause of death” in patients with diabetes, said Dr. Butler, professor and chairman of medicine at the University of Mississippi in Jackson.
“Thanks to the cardiovascular outcome trials, we now have a much broader and deeper appreciation of heart failure and renal disease as integral components of the cardiovascular-renal spectrum in people with diabetes,” said Subodh Verma, MD, a professor at the University of Toronto and cardiac surgeon at St. Michael’s Hospital in Toronto. Dr. Braunwald spelled out in his talk some of the interrelationships of diabetes, heart failure, and renal dysfunction that together produce a downward-spiraling vicious circle for patients, a pathophysiological process that clinicians can now short-circuit by treatment with a SGLT2 inhibitor.
Cardiovascular outcome trials show the way
In the context of antihyperglycemic drugs, the “cardiovascular outcome trials” refers to a series of large trials mandated by the Food and Drug Administration in 2008 to assess the cardiovascular disease effects of new agents coming onto the U.S. market to treat type 2 diabetes mellitus (T2DM). By the time Dr. Verma spoke at the AHA meeting, he could cite reported results from 12 of these trials: 5 different drugs in the GLP-1 RA class, 4 drugs in the dipeptidyl peptidase-4 (DPP-4) inhibitor class, and 3 drugs from the SGLT2 inhibitor class. Dr. Verma summed what the findings have shown.
The four tested DDP-4 inhibitors (alogliptin, linagliptin, saxagliptin, and sitagliptin) consistently showed neutrality for the primary outcome of major adverse cardiovascular disease events (MACE), constituted by cardiovascular disease death, MI, or stroke.
The five tested GLP-1 RAs (albiglutide, exenatide, liraglutide, lixisenatide, and semaglutide) showed a mixed pattern of MACE results that seemed to be linked with the subclass the drug fell into. The two exedin-4–based drugs, exenatide and lixisenatide, each showed a statistically neutral effect for MACE, as well as collectively in a combined analysis. In contrast, three human GLP-1–based drugs, albiglutide, liraglutide, and semaglutide, each showed a consistent, statistically-significant MACE reduction in their respective outcome trials, and collectively they showed a highly significant 18% reduction in MACE, compared with placebo, Dr. Verma said. Further, recent analysis by Dr. Verma that used data from liraglutide treatment in the LEADER trial showed the MACE benefit occurred only among enrolled patients treated with liraglutide who had established atherosclerotic cardiovascular disease (ASCVD). Patients enrolled in the trial with only multiple risk factors (in addition to having T2DM) but without established ASCVD showed no significant benefit from liraglutide treatment for the MACE endpoint, compared with control patients.
Recently a press-release announcement of results from a sixth GLP-1 RA, dulaglutide, in the REWIND trial of MACE outcomes suggested that a drug in this class could have broader effect. The majority, 69%, of the 9,901 patients with T2DM enrolled in REWIND had risk factors but not established ASCVD at enrollment. A Nov. 5, 2018, statement from the company developing this drug, Lilly, reported that the study overall produced a statistically significant reduction in MACE, although it provided no additional details. As the released noted, this made REWIND the first trial to show a MACE benefit from a drug in the GLP-1 RA class in patients without established ASCVD.
The MACE outcome results from the three SGLT2 inhibitor trials showed a similar pattern as liraglutide: In patients with established ASCVD, the drugs individually each produced a MACE reduction, although dapagliflozin just missed having a statistically significant reduction. Collectively, the three drugs showed a statistically significant, 14% relative risk reduction for MACE, compared with control patients. But among patients with multiple risk factors only, but without established ASCVD, included in two of the three trials (CANVAS and DECLARE-TIMI 58), the results showed both individually and collectively a neutral MACE effect.
But unlike the other antihyperglycemic drugs tested in the cardiovascular outcome trials, the SGLT2 inhibitors have shown two additional, highly important secondary outcomes: a consistent reduction in hospitalization for heart failure and a consistent reduction in renal-disease progression.
A meta-analysis of the three SGLT2 inhibitor trials published coincident with the release of the DECLARE-TIMI 58 results showed that, for the outcome of either cardiovascular death or hospitalization for heart failure, the SGLT2 inhibitors collectively showed a significant 29% relative decrease in this incidence among patients with a history of heart failure, and a significant 21% relative decrease among patients without history of heart failure (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32590-X). Among the subset of patients with established ASCVD, treatment with a SGLT2 inhibitor across all three trials showed a significant 16% relative risk reduction, and in the subset with multiple risk factors but no established ASCVD, the two SGLT2 inhibitors collectively produced a 16% relative cut in cardiovascular death or heart failure hospitalization with a P value of .06. Finally, the Lancet meta-analysis showed that, for a combined endpoint that reflected renal worsening, the SGLT2 inhibitors showed a significant relative reduction of about 45% in both the subgroup of patients with established ASCVD and in the subgroup of those with just risk factors.
“This is a big step forward for patients with multiple risk factors and diabetes but without ASCVD, that both renal disease and hospitalization for heart failure are sensitive” to the SGLT2 inhibitors, Dr. Verma noted. “We see renal protection and reduction of heart failure hospitalization across both primary and secondary prevention patients, with no need to distinguish them based on ASCVD.” In contrast, he noted, the MACE benefit from the SGLT2 inhibitors seems limited to patients with ASCVD. The day before making this point in a talk during the meeting, Dr. Verma had published the same message in a commentary (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32824-1).
Although the “nomenclature of primary versus secondary prevention is appropriate for atherosclerotic outcomes, it is likely to be inappropriate for a person with type 2 diabetes who is at risk of hospitalization for heart failure and renal disease,” Dr. Verma wrote with his associates in the commentary.
What it means for clinicians
The upshot of all of these cardiovascular outcome trial results that came out over the past 3 years has been a new appreciation of how antihyperglycemic drugs can have cardiovascular and renal benefits that transcend their effects on glycemia. The evidence has put the SGLT2 inhibitors and GLP-1 RAs on track to challenge, and potentially displace, metformin as the top drug to prescribe for patients with T2DM.
Clinicians should realize that they should prescribe SGLT2 inhibitors and selected GLP-1 RAs “as early as metformin in patients with established ASCVD,” said Dr. Verma. “For patients with recalcitrant atherosclerotic disease and a history of MI and ischemia, I’d primarily treat with a GLP-1 RA. In a patient with left ventricular dysfunction or evidence of heart failure, I’d use an SGLT2 inhibitor. But it’s not a fight between these two. You could treat a patients with type 2 diabetes with both classes,” although the practicality of this approach is limited by the high cost of these drugs.
The SGLT2 inhibitors “should now be considered as first-line therapy after metformin in most people with type 2 diabetes, irrespective of whether or not they have established atherosclerotic vascular disease, chronic kidney disease, or heart failure,” he and his associates wrote in their recent commentary.
“What I struggle with the most is how we prioritize and individualize secondary-prevention therapies based on risk for ischemia and heart failure. Some therapies [the SGLT2 inhibitors] are predominantly for heart failure prevention, and some [the GLP-1 RAs] are primarily for ischemia. How do we choose when a patient cannot afford to take both? Does a combination of a SGLT2 inhibitor and a GLP-1 RA offer the greatest CVD benefit? We need to test this in a trial. And will metformin be displaced as first-line treatment?” Dr. Verma asked.
“The day will probably come when, for maximal protection, you treat with both classes. But right now we’re forced to choose because of the cost,” said John McMurray, MD, professor of cardiology at the University of Glasgow, in a talk during the meeting.
As to specifically which SGLT2 inhibitor to prescribe, “they all look pretty much the same” in the newly published meta-analysis, Dr. McMurray said, although he noted that safety differences among agents in the class remain possible.
“For patients similar to those studied in the three SGLT2 inhibitor trials, clinicians should use one of these drugs to reduce the risk for incident heart failure, irrespective of their effect on MACE,” said Dr. Butler. Reducing the risk for incident heart failure and of progressive renal dysfunction are two new goals for antihyperglycemic therapy that now overlay the long-standing goals of controlling glycemia and reducing cardiovascular disease risk and the more recent goals of cutting cardiovascular disease mortality and cutting the risk for a MACE event.
A current limitation for practice is that the none of the three drug companies that market the tested SGLT2 inhibitor drugs has sought regulatory approval for an indication of reducing the risk for heart failure hospitalization. Despite that, “these drugs should be used for renal protection and reducing heart failure hospitalizations,” Dr. Butler said. “We need to start thinking about this and not get lost thinking about only their MACE effect because, when you focus on MACE, there is a competition between the SGLT2 inhibitors and the GLP-1 RA. If we think of GLP-1 RAs as drugs to prevent MACE, and SGLT2 inhibitors as drugs that primarily prevent heart failure and renal dysfunction, then there is no competition. Perhaps combined treatment is where we need to go,” he said in an interview.
But the enthusiasm that experts like Dr. Butler, Dr. McMurray, and Dr. Verma have for wider use of both classes of drugs in appropriate patients is not necessarily matched right now among many community physicians. Cardiologist David J. Becker, MD, is an example of the clinicians who appreciate the growing evidence that supports wider use of these antihyperglycemic drugs but remain uneasy about applying this evidence in their practice.
Dr. Becker, associate director of the Preventive and Integrative Heart Health Program of the Temple Heart and Vascular Institute in Philadelphia, writes a column for the Philadelphia Inquirer on medical care. In a December 2018 piece, he said “like most cardiologists, I ‘don’t do diabetes’ – because it’s not my expertise. The new drugs, however, mean I need to learn more” about treating these patients. “The problem: There are so many of these medications that they present a bewildering choice for patients and doctors.”
Dr. Becker cited several barriers he sees for himself and his nonendocrinologist colleagues to prescribe these drugs – and for patients to take them:
- High cost, with prices that run close to $20/day for each medication.
- A thicket of names and choices that “lead to confusion and paralysis,” which has been exacerbated by “advertising wars” among competing drug companies.
- Cardiologists and primary care physicians usually defer to endocrinologists to prescribe these drugs, but most patients with T2DM aren’t seen by endocrinologists. The result: “Few doctors prescribe them.”
The cardiovascular disease benefits of these drugs have not been adequately promoted. Until that changes, “cardiologists like me will not realize their importance,” Dr. Becker concluded.
While christening the new diabetocardiology subspecialty, Dr. Braunwald placed the onus for managing this emerging facet of diabetes largely outside the scope of endocrinology.
“We can’t call in a consultant every time we have a patient with diabetes; it would bankrupt the system,” he said. Training of cardiologists now needs to include several months of treating patients with diabetes, Dr. Braunwald advised, just like 30 or so years ago when cardiologists like himself had to become more familiar with blood clotting to better manage thrombotic disease.
Dr. Braunwald has been a consultant to Cardurion, Myokardia, and Sanofi; an advisor to Endcardia; and has received research funding from AstraZeneca, Daiishi Sankyo, and Novartis. Dr. Butler has been a consultant or advisor to AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Janssen, Merck, Novartis, Novo Nordisk, and Sanofi. Dr. Verma has received honoraria and research funding from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, NovoNordisk, Sanofi, and Valeant. Dr. McMurray has received research funding from 12 companies. Dr. Becker had no disclosures.
REPORTING FROM THE AHA SCIENTIFIC SESSIONS