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ROCKVILLE, MD. – In a 12-11 vote, a Food and Drug Administration advisory panel just barely came down in favor of the agency adding a new labeling entry to the already-approved diabetes drug empagliflozin (Jardiance) that would say the drug reduces cardiovascular mortality.
While several members of the panel wished the FDA’s staff good luck in weighing both the evidence and the advisory committee’s closely split endorsement when deciding whether to grant this unprecedented labeling to a diabetes drug, the fact that a majority of panelists favored this course marked a watershed moment in the development of new agents for treating hyperglycemia.
“It’s the first time we have evidence that a diabetes drug can reduce cardiovascular risk. That’s never been seen before, and it’s huge,” said Marvin A. Konstam, MD, a temporary member of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) and chief physician executive of the cardiovascular center at Tufts Medical Center in Boston. “The question is whether or not this effect is real, and the vote was 50-50, but I think there is a good chance it’s real, and, if so, it’s a game changer,” Dr. Konstam said in an interview. He voted in favor of the new labeling, and, like many of his colleagues on the panel, he admitted to agonizing over the decision during the postvote comment period.
What he and the other committee members struggled with was a remarkably strong effect by empagliflozin on reducing cardiovascular mortality by a relative 38%, compared with placebo, in more than 7,000 patients with type 2 diabetes selected for their high cardiovascular disease risk. The major sticking point was that the study enrolled patients into a randomized, placebo-controlled trial that was primarily designed to test the drug’s cardiovascular safety and not its efficacy, and where cardiovascular death was not even a prespecified secondary endpoint.
“It’s very hard to go from safety to superiority in one study,” said Peter W.F. Wilson, MD, who voted against the added indication. Like many panel members who voted no, Dr. Wilson said that any claim to preventing cardiovascular mortality with empagliflozin should meet the standard FDA requirement to have consistent results from at least two studies. “This is the first drug in its class [the sodium-glucose cotransporter 2 inhibitors], and we should have a high bar for the quality of the evidence,” said Dr. Wilson, professor of medicine and public health at Emory University in Atlanta.
“There is substantial evidence [to support the mortality claim], but not yet to the extent to put it on the label,” said another voter on the no side, Judith Fradkin, MD, also a temporary committee member and director of the division of diabetes, endocrinology and metabolic diseases at the National Institutes of Health. The data collected so far in favor of the mortality claim “are very compelling, but what I couldn’t get past is my long-standing belief that a positive result to a study’s secondary outcome is hypothesis generating. We need a second study to put this on the label,” Dr. Fradkin said.
That dramatic and highly meaningful clinical effect of empagliflozin on cardiovascular mortality jumped out at the investigators who ran the EMPA-REG OUTCOME trial as well as to many others from the moment the results had their unveiling less than a year ago, at the annual meeting of the European Association for the Study of Diabetes in Stockholm, and in a concurrently published article (N Engl J Med. 2015 Nov 26;373[22]:2117-28).
The primary efficacy endpoint placed into the EMPA-REG OUTCOME safety trial as the study developed following the 2008 FDA mandate for cardiovascular safety trials for all new hypoglycemic drugs was a three-part, combined-outcome endpoint of cardiovascular death, nonfatal MI, and nonfatal stroke. Although this primary, combined endpoint had a statistically significant but much more modest benefit with a 14% relative risk reduction, compared with placebo, “the benefit was all driven by the reduction in cardiovascular death that had an astonishing P value of less than .0001 with no suggestion of benefit or risk for MI or stroke,” said Stuart Pocock, PhD, professor of medical statistics at the London School of Hygiene and Tropical Medicine who appeared before the committee as a consultant brought in by the applicant, Boehringer Ingelheim.
The total 309 cardiovascular deaths seen during the study that led to this finding provided more data than most cardiovascular trials, and while in some respects, the cardiovascular benefit seemed “too good to be true,” it also turned out that “the data were so strong that they overwhelm skepticism,” Dr. Pocock told the panel while presenting some advanced statistical test results to prove this assertion. The trial results showed “overwhelming evidence of benefit, beyond a reasonable doubt,” and while cardiovascular death was just one part of the efficacy endpoint, “mortality merits special attention,” he said. The statistical analyses also showed an equally robust 32% relative risk reduction in all-cause mortality, and both the cardiovascular and all-cause death benefits seen in EMPA-REG OUTCOME were consistent across both dosages of empagliflozin tested in the study (10 mg and 25 mg daily) and across the sensitivity analyses applied by the investigators.
“These are convincing data, but I’m not comfortable enough that these robust data would be reproduced in a second trial,” said panel chair Robert J. Smith, MD, who voted against the indication.
An additional limitation acting against the proposed new labeling, according to several panel members, is that the mechanism by which empagliflozin might exert protection against cardiovascular death remains unknown, with no suggestion in the trial results that it acts by protecting patients against ischemic disease.
Current opinion also splits among clinicians on how empagliflozin, which has had FDA approval since 2014 as an option for treating type 2 diabetes, should be used in routine practice to treat diabetes patients with high cardiovascular risk who match those enrolled in the EMPA-REG OUTCOME trial. Dr. Smith urged a cautious approach.
“I think it’s important [for prescribers] to wait to hear from the FDA. If the cardiovascular mortality benefit was proven, then it would be an important option given the magnitude of cardiovascular disease and death as a consequence of type 2 diabetes. But people should be cautious in drawing their own interpretations of the data,” Dr. Smith, professor of medicine at Brown University in Providence, R.I., said in an interview. For the time being, metformin remains the top oral drug for most of these patients because of its proven effectiveness and low cost, he added.
But others have already been active in prescribing empagliflozin to at-risk patients with type 2 diabetes based on last year’s EMPA-REG OUTCOME report.
“I am using it in addition to metformin and aggressive lifestyle changes in patients with established cardiovascular disease and uncontrolled type 2 diabetes,” commented Alison L. Bailey, MD, a cardiologist at the Erlanger Health System and University of Tennessee in Chattanooga. “A patient’s health insurance status must be taken into account as empagliflozin can be a significant financial burden, but if all other things are equal and cost is not prohibitive, I am definitely using this in my patients with type 2 diabetes and cardiovascular disease. I think there are enough data to warrant its use first line in patients who can get the drug without a financial burden,” she said in an interview.
Dr. Konstam cautioned that “just because empagliflozin may have a cardiovascular effect does not make it a cardiovascular drug. As a cardiologist I am not comfortable prescribing this drug. When it comes to diabetes management ,you need to take many things into consideration, most notably blood sugar and hemoglobin A1c,” which are usually best managed by a diabetologist or experienced primary care physician, he said.
Dr. Konstam, Dr. Wilson, Dr. Fradkin, and Dr. Smith had no relevant financial disclosures. Dr. Pocock is a consultant to Boehringer Ingelheim. Dr. Bailey has received research grants from CSL Behring.
On Twitter@mitchelzoler
ROCKVILLE, MD. – In a 12-11 vote, a Food and Drug Administration advisory panel just barely came down in favor of the agency adding a new labeling entry to the already-approved diabetes drug empagliflozin (Jardiance) that would say the drug reduces cardiovascular mortality.
While several members of the panel wished the FDA’s staff good luck in weighing both the evidence and the advisory committee’s closely split endorsement when deciding whether to grant this unprecedented labeling to a diabetes drug, the fact that a majority of panelists favored this course marked a watershed moment in the development of new agents for treating hyperglycemia.
“It’s the first time we have evidence that a diabetes drug can reduce cardiovascular risk. That’s never been seen before, and it’s huge,” said Marvin A. Konstam, MD, a temporary member of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) and chief physician executive of the cardiovascular center at Tufts Medical Center in Boston. “The question is whether or not this effect is real, and the vote was 50-50, but I think there is a good chance it’s real, and, if so, it’s a game changer,” Dr. Konstam said in an interview. He voted in favor of the new labeling, and, like many of his colleagues on the panel, he admitted to agonizing over the decision during the postvote comment period.
What he and the other committee members struggled with was a remarkably strong effect by empagliflozin on reducing cardiovascular mortality by a relative 38%, compared with placebo, in more than 7,000 patients with type 2 diabetes selected for their high cardiovascular disease risk. The major sticking point was that the study enrolled patients into a randomized, placebo-controlled trial that was primarily designed to test the drug’s cardiovascular safety and not its efficacy, and where cardiovascular death was not even a prespecified secondary endpoint.
“It’s very hard to go from safety to superiority in one study,” said Peter W.F. Wilson, MD, who voted against the added indication. Like many panel members who voted no, Dr. Wilson said that any claim to preventing cardiovascular mortality with empagliflozin should meet the standard FDA requirement to have consistent results from at least two studies. “This is the first drug in its class [the sodium-glucose cotransporter 2 inhibitors], and we should have a high bar for the quality of the evidence,” said Dr. Wilson, professor of medicine and public health at Emory University in Atlanta.
“There is substantial evidence [to support the mortality claim], but not yet to the extent to put it on the label,” said another voter on the no side, Judith Fradkin, MD, also a temporary committee member and director of the division of diabetes, endocrinology and metabolic diseases at the National Institutes of Health. The data collected so far in favor of the mortality claim “are very compelling, but what I couldn’t get past is my long-standing belief that a positive result to a study’s secondary outcome is hypothesis generating. We need a second study to put this on the label,” Dr. Fradkin said.
That dramatic and highly meaningful clinical effect of empagliflozin on cardiovascular mortality jumped out at the investigators who ran the EMPA-REG OUTCOME trial as well as to many others from the moment the results had their unveiling less than a year ago, at the annual meeting of the European Association for the Study of Diabetes in Stockholm, and in a concurrently published article (N Engl J Med. 2015 Nov 26;373[22]:2117-28).
The primary efficacy endpoint placed into the EMPA-REG OUTCOME safety trial as the study developed following the 2008 FDA mandate for cardiovascular safety trials for all new hypoglycemic drugs was a three-part, combined-outcome endpoint of cardiovascular death, nonfatal MI, and nonfatal stroke. Although this primary, combined endpoint had a statistically significant but much more modest benefit with a 14% relative risk reduction, compared with placebo, “the benefit was all driven by the reduction in cardiovascular death that had an astonishing P value of less than .0001 with no suggestion of benefit or risk for MI or stroke,” said Stuart Pocock, PhD, professor of medical statistics at the London School of Hygiene and Tropical Medicine who appeared before the committee as a consultant brought in by the applicant, Boehringer Ingelheim.
The total 309 cardiovascular deaths seen during the study that led to this finding provided more data than most cardiovascular trials, and while in some respects, the cardiovascular benefit seemed “too good to be true,” it also turned out that “the data were so strong that they overwhelm skepticism,” Dr. Pocock told the panel while presenting some advanced statistical test results to prove this assertion. The trial results showed “overwhelming evidence of benefit, beyond a reasonable doubt,” and while cardiovascular death was just one part of the efficacy endpoint, “mortality merits special attention,” he said. The statistical analyses also showed an equally robust 32% relative risk reduction in all-cause mortality, and both the cardiovascular and all-cause death benefits seen in EMPA-REG OUTCOME were consistent across both dosages of empagliflozin tested in the study (10 mg and 25 mg daily) and across the sensitivity analyses applied by the investigators.
“These are convincing data, but I’m not comfortable enough that these robust data would be reproduced in a second trial,” said panel chair Robert J. Smith, MD, who voted against the indication.
An additional limitation acting against the proposed new labeling, according to several panel members, is that the mechanism by which empagliflozin might exert protection against cardiovascular death remains unknown, with no suggestion in the trial results that it acts by protecting patients against ischemic disease.
Current opinion also splits among clinicians on how empagliflozin, which has had FDA approval since 2014 as an option for treating type 2 diabetes, should be used in routine practice to treat diabetes patients with high cardiovascular risk who match those enrolled in the EMPA-REG OUTCOME trial. Dr. Smith urged a cautious approach.
“I think it’s important [for prescribers] to wait to hear from the FDA. If the cardiovascular mortality benefit was proven, then it would be an important option given the magnitude of cardiovascular disease and death as a consequence of type 2 diabetes. But people should be cautious in drawing their own interpretations of the data,” Dr. Smith, professor of medicine at Brown University in Providence, R.I., said in an interview. For the time being, metformin remains the top oral drug for most of these patients because of its proven effectiveness and low cost, he added.
But others have already been active in prescribing empagliflozin to at-risk patients with type 2 diabetes based on last year’s EMPA-REG OUTCOME report.
“I am using it in addition to metformin and aggressive lifestyle changes in patients with established cardiovascular disease and uncontrolled type 2 diabetes,” commented Alison L. Bailey, MD, a cardiologist at the Erlanger Health System and University of Tennessee in Chattanooga. “A patient’s health insurance status must be taken into account as empagliflozin can be a significant financial burden, but if all other things are equal and cost is not prohibitive, I am definitely using this in my patients with type 2 diabetes and cardiovascular disease. I think there are enough data to warrant its use first line in patients who can get the drug without a financial burden,” she said in an interview.
Dr. Konstam cautioned that “just because empagliflozin may have a cardiovascular effect does not make it a cardiovascular drug. As a cardiologist I am not comfortable prescribing this drug. When it comes to diabetes management ,you need to take many things into consideration, most notably blood sugar and hemoglobin A1c,” which are usually best managed by a diabetologist or experienced primary care physician, he said.
Dr. Konstam, Dr. Wilson, Dr. Fradkin, and Dr. Smith had no relevant financial disclosures. Dr. Pocock is a consultant to Boehringer Ingelheim. Dr. Bailey has received research grants from CSL Behring.
On Twitter@mitchelzoler
ROCKVILLE, MD. – In a 12-11 vote, a Food and Drug Administration advisory panel just barely came down in favor of the agency adding a new labeling entry to the already-approved diabetes drug empagliflozin (Jardiance) that would say the drug reduces cardiovascular mortality.
While several members of the panel wished the FDA’s staff good luck in weighing both the evidence and the advisory committee’s closely split endorsement when deciding whether to grant this unprecedented labeling to a diabetes drug, the fact that a majority of panelists favored this course marked a watershed moment in the development of new agents for treating hyperglycemia.
“It’s the first time we have evidence that a diabetes drug can reduce cardiovascular risk. That’s never been seen before, and it’s huge,” said Marvin A. Konstam, MD, a temporary member of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) and chief physician executive of the cardiovascular center at Tufts Medical Center in Boston. “The question is whether or not this effect is real, and the vote was 50-50, but I think there is a good chance it’s real, and, if so, it’s a game changer,” Dr. Konstam said in an interview. He voted in favor of the new labeling, and, like many of his colleagues on the panel, he admitted to agonizing over the decision during the postvote comment period.
What he and the other committee members struggled with was a remarkably strong effect by empagliflozin on reducing cardiovascular mortality by a relative 38%, compared with placebo, in more than 7,000 patients with type 2 diabetes selected for their high cardiovascular disease risk. The major sticking point was that the study enrolled patients into a randomized, placebo-controlled trial that was primarily designed to test the drug’s cardiovascular safety and not its efficacy, and where cardiovascular death was not even a prespecified secondary endpoint.
“It’s very hard to go from safety to superiority in one study,” said Peter W.F. Wilson, MD, who voted against the added indication. Like many panel members who voted no, Dr. Wilson said that any claim to preventing cardiovascular mortality with empagliflozin should meet the standard FDA requirement to have consistent results from at least two studies. “This is the first drug in its class [the sodium-glucose cotransporter 2 inhibitors], and we should have a high bar for the quality of the evidence,” said Dr. Wilson, professor of medicine and public health at Emory University in Atlanta.
“There is substantial evidence [to support the mortality claim], but not yet to the extent to put it on the label,” said another voter on the no side, Judith Fradkin, MD, also a temporary committee member and director of the division of diabetes, endocrinology and metabolic diseases at the National Institutes of Health. The data collected so far in favor of the mortality claim “are very compelling, but what I couldn’t get past is my long-standing belief that a positive result to a study’s secondary outcome is hypothesis generating. We need a second study to put this on the label,” Dr. Fradkin said.
That dramatic and highly meaningful clinical effect of empagliflozin on cardiovascular mortality jumped out at the investigators who ran the EMPA-REG OUTCOME trial as well as to many others from the moment the results had their unveiling less than a year ago, at the annual meeting of the European Association for the Study of Diabetes in Stockholm, and in a concurrently published article (N Engl J Med. 2015 Nov 26;373[22]:2117-28).
The primary efficacy endpoint placed into the EMPA-REG OUTCOME safety trial as the study developed following the 2008 FDA mandate for cardiovascular safety trials for all new hypoglycemic drugs was a three-part, combined-outcome endpoint of cardiovascular death, nonfatal MI, and nonfatal stroke. Although this primary, combined endpoint had a statistically significant but much more modest benefit with a 14% relative risk reduction, compared with placebo, “the benefit was all driven by the reduction in cardiovascular death that had an astonishing P value of less than .0001 with no suggestion of benefit or risk for MI or stroke,” said Stuart Pocock, PhD, professor of medical statistics at the London School of Hygiene and Tropical Medicine who appeared before the committee as a consultant brought in by the applicant, Boehringer Ingelheim.
The total 309 cardiovascular deaths seen during the study that led to this finding provided more data than most cardiovascular trials, and while in some respects, the cardiovascular benefit seemed “too good to be true,” it also turned out that “the data were so strong that they overwhelm skepticism,” Dr. Pocock told the panel while presenting some advanced statistical test results to prove this assertion. The trial results showed “overwhelming evidence of benefit, beyond a reasonable doubt,” and while cardiovascular death was just one part of the efficacy endpoint, “mortality merits special attention,” he said. The statistical analyses also showed an equally robust 32% relative risk reduction in all-cause mortality, and both the cardiovascular and all-cause death benefits seen in EMPA-REG OUTCOME were consistent across both dosages of empagliflozin tested in the study (10 mg and 25 mg daily) and across the sensitivity analyses applied by the investigators.
“These are convincing data, but I’m not comfortable enough that these robust data would be reproduced in a second trial,” said panel chair Robert J. Smith, MD, who voted against the indication.
An additional limitation acting against the proposed new labeling, according to several panel members, is that the mechanism by which empagliflozin might exert protection against cardiovascular death remains unknown, with no suggestion in the trial results that it acts by protecting patients against ischemic disease.
Current opinion also splits among clinicians on how empagliflozin, which has had FDA approval since 2014 as an option for treating type 2 diabetes, should be used in routine practice to treat diabetes patients with high cardiovascular risk who match those enrolled in the EMPA-REG OUTCOME trial. Dr. Smith urged a cautious approach.
“I think it’s important [for prescribers] to wait to hear from the FDA. If the cardiovascular mortality benefit was proven, then it would be an important option given the magnitude of cardiovascular disease and death as a consequence of type 2 diabetes. But people should be cautious in drawing their own interpretations of the data,” Dr. Smith, professor of medicine at Brown University in Providence, R.I., said in an interview. For the time being, metformin remains the top oral drug for most of these patients because of its proven effectiveness and low cost, he added.
But others have already been active in prescribing empagliflozin to at-risk patients with type 2 diabetes based on last year’s EMPA-REG OUTCOME report.
“I am using it in addition to metformin and aggressive lifestyle changes in patients with established cardiovascular disease and uncontrolled type 2 diabetes,” commented Alison L. Bailey, MD, a cardiologist at the Erlanger Health System and University of Tennessee in Chattanooga. “A patient’s health insurance status must be taken into account as empagliflozin can be a significant financial burden, but if all other things are equal and cost is not prohibitive, I am definitely using this in my patients with type 2 diabetes and cardiovascular disease. I think there are enough data to warrant its use first line in patients who can get the drug without a financial burden,” she said in an interview.
Dr. Konstam cautioned that “just because empagliflozin may have a cardiovascular effect does not make it a cardiovascular drug. As a cardiologist I am not comfortable prescribing this drug. When it comes to diabetes management ,you need to take many things into consideration, most notably blood sugar and hemoglobin A1c,” which are usually best managed by a diabetologist or experienced primary care physician, he said.
Dr. Konstam, Dr. Wilson, Dr. Fradkin, and Dr. Smith had no relevant financial disclosures. Dr. Pocock is a consultant to Boehringer Ingelheim. Dr. Bailey has received research grants from CSL Behring.
On Twitter@mitchelzoler
AT AN FDA EMDAC MEETING
