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Diabetes drug development entered a new era in 2007 when a meta-analysis of 42 studies that had compared rosiglitazone with other drugs in a total of nearly 28,000 patients suggested that rosiglitazone treatment led to significantly increased rates of cardiovascular death and myocardial infarction.
Based largely on that, the Food and Drug Administration in 2008 issued recommendations to companies developing new diabetes drugs to run large-scale trials aimed at assessing their cardiovascular effects.
In 2011, the FDA placed restrictions on prescribing rosiglitazone, and U.S. use of the drug plummeted. (An FDA panel voted in June to relax some of the restrictions the agency had imposed.)
Some consequences of the long shadow cast by the rosiglitazone experience played out in talks at the annual congress of the European Society for the Study of Diabetes in September, as well as at the annual congress of the European Society of Cardiology a few weeks before that. The new data show just how painstaking investigators have become in trying to parse out hints of cardiovascular danger lurking in masses of megatrial data.
Heart failure haunts DPP-4 inhibitors
At ESC, as well as in a pair of simultaneously published articles, researchers reported results from two large trials designed to follow the FDA recommendations and assess cardiovascular safety for two new selective dipeptidyl peptidase-4 (DPP-4) inhibitors, saxagliptin (Onglyza) and alogliptin, in patients with type 2 diabetes.
Saxagliptin was the drug with the red-flag signal, while alogliptin faced guilt by association. The saxagliptin study, SAVOR-TIMI 53, used patients with either an established history of cardiovascular disease (CVD) or multiple CVD risk factors. The study’s primary safety endpoint, the combined rate of CVD death, nonfatal myocardial infarction, or nonfatal stroke during 2 years of follow-up, was virtually identical in the two groups, 7.3% in the saxagliptin patients and 7.2% in the controls.
The study’s secondary safety endpoint, which included the primary combined plus other endpoints such as need for revascularization and hospitalization for heart failure, was also similar in the two study arms, with this expanded combined endpoint occurring in 12.8% of the saxagliptin patients and 12.4% of the controls (N. Engl. J. Med. 2013;369:1317-26).
The whisper of a saxagliptin problem was in just one secondary, individual safety endpoint, hospitalizations for heart failure. These occurred in 3.5% of the saxagliptin patients and in 2.8% of controls, a statistically significant difference. Further data presented at EASD showed that this difference clustered predominantly in the subgroup of patients who entered the study with presumed heart failure, based on having a blood level of NT-pro brain natriuretic peptide of at least 333, about 25% of patients in both treatment arms (although the investigators identified heart failure in only 13% of enrolled patients). Within this subgroup, heart failure–associated hospitalizations occurred in 10.9% of the saxagliptin patients and 8.9% of the controls, a statistically significant difference, reported Dr. Deepak L. Bhatt, one of the investigators for the SAVOR-TIMI 53 study, which randomized more than 16,000 patients.
In contrast, the alogliptin study, EXAMINE, which randomized more than 5,000 patients with type 2 diabetes and a recent acute coronary syndrome event to treatment with alogliptin or placebo, found no real confirmation of this problem (N. Engl. J. Med. 2013;369:1327-35).
After the early-September report of this saxagliptin and heart failure hospitalization signal, the EXAMINE researchers went back to their data to specifically look at this issue, Dr. William B. White, the lead investigator, said when he presented the new findings at EASD. During a median of 18 months of follow-up, the rate of hospitalizations for heart failure was 3.1% in the alogliptin group and 2.9% in the placebo group, a difference that was not statistically significant, although it trended just slightly toward an alogliptin problem. Among the subgroup of patients who entered EXAMINE with a history of heart failure, the rate of the combined cardiovascular safety endpoint of CV death, nonfatal MI, or nonfatal stroke was 18% in the alogliptin group and 22% in the placebo group, a difference that was not statistically significant.
Despite the absence of any apparent heart failure–hospitalization effect in EXAMINE, Dr. Naveed Sattar, the invited discussant for the two reports at EASD, meta-analyzed the heart failure–hospitalization results from both studies, and found a combined, 24% relative increase in this outcome for the two DPP-4 inhibitors combined, a statistically significant effect largely driven toward significance by the underlying statistical significance in the saxagliptin study; the alogliptin results couldn’t resolve this difference since they trended in the same direction. Dr. Sattar concluded that it raised enough doubt about the safety of this entire drug class in patients with pre-existing heart failure to recommend not using drugs from this class in patients with any indication of heart failure – regardless of severity – until the apparent link received further scrutiny. Dr. Bhatt promised a report with further information on the heart failure issue at the American Heart Association Scientific Sessions in November.
Signals for canagliflozin, too?
SAVOR-TIMI 53 and EXAMINE provide the first results from what are more than a dozen large studies – involving more than 100,000 patients – launched recently to look for adverse cardiovascular effects from drugs in six different diabetes drug classes, according to Dr. Sanjay Kaul, who also spoke at EASD. He presented results from a meta-analysis he performed on results from nine phase III and phase II trials of canagliflozin (Invokana), an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class and approved by the FDA last March for treatment of type 2 diabetes, the first drug in that class to get U.S. marketing approval.
In the largest of these trials, CANVAS – the cardiovascular-assessment study for canagliflozin set up by the drug’s developer, Janssen – treatment with canagliflozin linked with a statistically significant, sixfold increase in cardiovascular events during the first 30 days of treatment, a link that then disappeared with longer-term treatment in patients with high CV risk. (Complete results from CANVAS have not yet been reported.) But Dr. Kaul did not see a similar excess in the other eight studies.
The canagliflozin meta-analysis also showed a nonsignificant, 46% increased risk of stroke in patients on the drug, a signal not seen in any other individual cardiovascular endpoint. Dr. Kaul analyzed data from 14 phase II and III trials for a second SGLT2 inhibitor drug, dapagliflozin, which showed no suggestion of causing any cardiovascular risk.
The canagliflozin risk signals are not reasons to stop using the drug or to withdraw it from the market, said Dr. Kaul, a member of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee. The early signal of risk in CANVAS was not seen in any other study, and it may have been a statistical artifact, he said.
He said that signals of risk must be considered relative to a drug’s benefit. Applying the same standard of cardiovascular harm to drugs that are highly effective and to drugs that are not very effective "doesn’t make sense," he said. "A risk-benefit trade-off depends on the benefit. If you have a diabetes drug that lowers hemoglobin A1c by 1.5%-2% I’m willing to accept greater harm than I would from a drug that produced a 0.5% drop in hemoglobin A1c."
A final rosiglitazone thought
Dr. Kaul also made this observation about the rosiglitazone experience, which in retrospect produced "insufficient evidence to either incriminate or exonerate rosiglitazone," he said.
"That a diabetes drug [rosiglitazone] could have become a blockbuster without any established outcome benefits does not reflect well on the drug development and approval process. Equally lamentable is that this drug was virtually killed based on insufficient evidence and entrenched opinions."
Dr. Bhatt has received research grants from several companies, including AstraZeneca and Bristol-Myers Squibb (BMS), which market saxagliptin, and Takeda, maker of alogliptin. Dr. White is a safety consultant for several companies, including AstraZeneca and Takeda. Dr. Sattar is a consultant to several pharmaceutical firms, including AstraZeneca and BMS. Dr. Kaul is a consultant to Novo Nordisk, Sanofi, and Boehringer Ingelheim, and owns stock in Johnson & Johnson.
On Twitter @mitchelzoler
Diabetes drug development entered a new era in 2007 when a meta-analysis of 42 studies that had compared rosiglitazone with other drugs in a total of nearly 28,000 patients suggested that rosiglitazone treatment led to significantly increased rates of cardiovascular death and myocardial infarction.
Based largely on that, the Food and Drug Administration in 2008 issued recommendations to companies developing new diabetes drugs to run large-scale trials aimed at assessing their cardiovascular effects.
In 2011, the FDA placed restrictions on prescribing rosiglitazone, and U.S. use of the drug plummeted. (An FDA panel voted in June to relax some of the restrictions the agency had imposed.)
Some consequences of the long shadow cast by the rosiglitazone experience played out in talks at the annual congress of the European Society for the Study of Diabetes in September, as well as at the annual congress of the European Society of Cardiology a few weeks before that. The new data show just how painstaking investigators have become in trying to parse out hints of cardiovascular danger lurking in masses of megatrial data.
Heart failure haunts DPP-4 inhibitors
At ESC, as well as in a pair of simultaneously published articles, researchers reported results from two large trials designed to follow the FDA recommendations and assess cardiovascular safety for two new selective dipeptidyl peptidase-4 (DPP-4) inhibitors, saxagliptin (Onglyza) and alogliptin, in patients with type 2 diabetes.
Saxagliptin was the drug with the red-flag signal, while alogliptin faced guilt by association. The saxagliptin study, SAVOR-TIMI 53, used patients with either an established history of cardiovascular disease (CVD) or multiple CVD risk factors. The study’s primary safety endpoint, the combined rate of CVD death, nonfatal myocardial infarction, or nonfatal stroke during 2 years of follow-up, was virtually identical in the two groups, 7.3% in the saxagliptin patients and 7.2% in the controls.
The study’s secondary safety endpoint, which included the primary combined plus other endpoints such as need for revascularization and hospitalization for heart failure, was also similar in the two study arms, with this expanded combined endpoint occurring in 12.8% of the saxagliptin patients and 12.4% of the controls (N. Engl. J. Med. 2013;369:1317-26).
The whisper of a saxagliptin problem was in just one secondary, individual safety endpoint, hospitalizations for heart failure. These occurred in 3.5% of the saxagliptin patients and in 2.8% of controls, a statistically significant difference. Further data presented at EASD showed that this difference clustered predominantly in the subgroup of patients who entered the study with presumed heart failure, based on having a blood level of NT-pro brain natriuretic peptide of at least 333, about 25% of patients in both treatment arms (although the investigators identified heart failure in only 13% of enrolled patients). Within this subgroup, heart failure–associated hospitalizations occurred in 10.9% of the saxagliptin patients and 8.9% of the controls, a statistically significant difference, reported Dr. Deepak L. Bhatt, one of the investigators for the SAVOR-TIMI 53 study, which randomized more than 16,000 patients.
In contrast, the alogliptin study, EXAMINE, which randomized more than 5,000 patients with type 2 diabetes and a recent acute coronary syndrome event to treatment with alogliptin or placebo, found no real confirmation of this problem (N. Engl. J. Med. 2013;369:1327-35).
After the early-September report of this saxagliptin and heart failure hospitalization signal, the EXAMINE researchers went back to their data to specifically look at this issue, Dr. William B. White, the lead investigator, said when he presented the new findings at EASD. During a median of 18 months of follow-up, the rate of hospitalizations for heart failure was 3.1% in the alogliptin group and 2.9% in the placebo group, a difference that was not statistically significant, although it trended just slightly toward an alogliptin problem. Among the subgroup of patients who entered EXAMINE with a history of heart failure, the rate of the combined cardiovascular safety endpoint of CV death, nonfatal MI, or nonfatal stroke was 18% in the alogliptin group and 22% in the placebo group, a difference that was not statistically significant.
Despite the absence of any apparent heart failure–hospitalization effect in EXAMINE, Dr. Naveed Sattar, the invited discussant for the two reports at EASD, meta-analyzed the heart failure–hospitalization results from both studies, and found a combined, 24% relative increase in this outcome for the two DPP-4 inhibitors combined, a statistically significant effect largely driven toward significance by the underlying statistical significance in the saxagliptin study; the alogliptin results couldn’t resolve this difference since they trended in the same direction. Dr. Sattar concluded that it raised enough doubt about the safety of this entire drug class in patients with pre-existing heart failure to recommend not using drugs from this class in patients with any indication of heart failure – regardless of severity – until the apparent link received further scrutiny. Dr. Bhatt promised a report with further information on the heart failure issue at the American Heart Association Scientific Sessions in November.
Signals for canagliflozin, too?
SAVOR-TIMI 53 and EXAMINE provide the first results from what are more than a dozen large studies – involving more than 100,000 patients – launched recently to look for adverse cardiovascular effects from drugs in six different diabetes drug classes, according to Dr. Sanjay Kaul, who also spoke at EASD. He presented results from a meta-analysis he performed on results from nine phase III and phase II trials of canagliflozin (Invokana), an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class and approved by the FDA last March for treatment of type 2 diabetes, the first drug in that class to get U.S. marketing approval.
In the largest of these trials, CANVAS – the cardiovascular-assessment study for canagliflozin set up by the drug’s developer, Janssen – treatment with canagliflozin linked with a statistically significant, sixfold increase in cardiovascular events during the first 30 days of treatment, a link that then disappeared with longer-term treatment in patients with high CV risk. (Complete results from CANVAS have not yet been reported.) But Dr. Kaul did not see a similar excess in the other eight studies.
The canagliflozin meta-analysis also showed a nonsignificant, 46% increased risk of stroke in patients on the drug, a signal not seen in any other individual cardiovascular endpoint. Dr. Kaul analyzed data from 14 phase II and III trials for a second SGLT2 inhibitor drug, dapagliflozin, which showed no suggestion of causing any cardiovascular risk.
The canagliflozin risk signals are not reasons to stop using the drug or to withdraw it from the market, said Dr. Kaul, a member of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee. The early signal of risk in CANVAS was not seen in any other study, and it may have been a statistical artifact, he said.
He said that signals of risk must be considered relative to a drug’s benefit. Applying the same standard of cardiovascular harm to drugs that are highly effective and to drugs that are not very effective "doesn’t make sense," he said. "A risk-benefit trade-off depends on the benefit. If you have a diabetes drug that lowers hemoglobin A1c by 1.5%-2% I’m willing to accept greater harm than I would from a drug that produced a 0.5% drop in hemoglobin A1c."
A final rosiglitazone thought
Dr. Kaul also made this observation about the rosiglitazone experience, which in retrospect produced "insufficient evidence to either incriminate or exonerate rosiglitazone," he said.
"That a diabetes drug [rosiglitazone] could have become a blockbuster without any established outcome benefits does not reflect well on the drug development and approval process. Equally lamentable is that this drug was virtually killed based on insufficient evidence and entrenched opinions."
Dr. Bhatt has received research grants from several companies, including AstraZeneca and Bristol-Myers Squibb (BMS), which market saxagliptin, and Takeda, maker of alogliptin. Dr. White is a safety consultant for several companies, including AstraZeneca and Takeda. Dr. Sattar is a consultant to several pharmaceutical firms, including AstraZeneca and BMS. Dr. Kaul is a consultant to Novo Nordisk, Sanofi, and Boehringer Ingelheim, and owns stock in Johnson & Johnson.
On Twitter @mitchelzoler
Diabetes drug development entered a new era in 2007 when a meta-analysis of 42 studies that had compared rosiglitazone with other drugs in a total of nearly 28,000 patients suggested that rosiglitazone treatment led to significantly increased rates of cardiovascular death and myocardial infarction.
Based largely on that, the Food and Drug Administration in 2008 issued recommendations to companies developing new diabetes drugs to run large-scale trials aimed at assessing their cardiovascular effects.
In 2011, the FDA placed restrictions on prescribing rosiglitazone, and U.S. use of the drug plummeted. (An FDA panel voted in June to relax some of the restrictions the agency had imposed.)
Some consequences of the long shadow cast by the rosiglitazone experience played out in talks at the annual congress of the European Society for the Study of Diabetes in September, as well as at the annual congress of the European Society of Cardiology a few weeks before that. The new data show just how painstaking investigators have become in trying to parse out hints of cardiovascular danger lurking in masses of megatrial data.
Heart failure haunts DPP-4 inhibitors
At ESC, as well as in a pair of simultaneously published articles, researchers reported results from two large trials designed to follow the FDA recommendations and assess cardiovascular safety for two new selective dipeptidyl peptidase-4 (DPP-4) inhibitors, saxagliptin (Onglyza) and alogliptin, in patients with type 2 diabetes.
Saxagliptin was the drug with the red-flag signal, while alogliptin faced guilt by association. The saxagliptin study, SAVOR-TIMI 53, used patients with either an established history of cardiovascular disease (CVD) or multiple CVD risk factors. The study’s primary safety endpoint, the combined rate of CVD death, nonfatal myocardial infarction, or nonfatal stroke during 2 years of follow-up, was virtually identical in the two groups, 7.3% in the saxagliptin patients and 7.2% in the controls.
The study’s secondary safety endpoint, which included the primary combined plus other endpoints such as need for revascularization and hospitalization for heart failure, was also similar in the two study arms, with this expanded combined endpoint occurring in 12.8% of the saxagliptin patients and 12.4% of the controls (N. Engl. J. Med. 2013;369:1317-26).
The whisper of a saxagliptin problem was in just one secondary, individual safety endpoint, hospitalizations for heart failure. These occurred in 3.5% of the saxagliptin patients and in 2.8% of controls, a statistically significant difference. Further data presented at EASD showed that this difference clustered predominantly in the subgroup of patients who entered the study with presumed heart failure, based on having a blood level of NT-pro brain natriuretic peptide of at least 333, about 25% of patients in both treatment arms (although the investigators identified heart failure in only 13% of enrolled patients). Within this subgroup, heart failure–associated hospitalizations occurred in 10.9% of the saxagliptin patients and 8.9% of the controls, a statistically significant difference, reported Dr. Deepak L. Bhatt, one of the investigators for the SAVOR-TIMI 53 study, which randomized more than 16,000 patients.
In contrast, the alogliptin study, EXAMINE, which randomized more than 5,000 patients with type 2 diabetes and a recent acute coronary syndrome event to treatment with alogliptin or placebo, found no real confirmation of this problem (N. Engl. J. Med. 2013;369:1327-35).
After the early-September report of this saxagliptin and heart failure hospitalization signal, the EXAMINE researchers went back to their data to specifically look at this issue, Dr. William B. White, the lead investigator, said when he presented the new findings at EASD. During a median of 18 months of follow-up, the rate of hospitalizations for heart failure was 3.1% in the alogliptin group and 2.9% in the placebo group, a difference that was not statistically significant, although it trended just slightly toward an alogliptin problem. Among the subgroup of patients who entered EXAMINE with a history of heart failure, the rate of the combined cardiovascular safety endpoint of CV death, nonfatal MI, or nonfatal stroke was 18% in the alogliptin group and 22% in the placebo group, a difference that was not statistically significant.
Despite the absence of any apparent heart failure–hospitalization effect in EXAMINE, Dr. Naveed Sattar, the invited discussant for the two reports at EASD, meta-analyzed the heart failure–hospitalization results from both studies, and found a combined, 24% relative increase in this outcome for the two DPP-4 inhibitors combined, a statistically significant effect largely driven toward significance by the underlying statistical significance in the saxagliptin study; the alogliptin results couldn’t resolve this difference since they trended in the same direction. Dr. Sattar concluded that it raised enough doubt about the safety of this entire drug class in patients with pre-existing heart failure to recommend not using drugs from this class in patients with any indication of heart failure – regardless of severity – until the apparent link received further scrutiny. Dr. Bhatt promised a report with further information on the heart failure issue at the American Heart Association Scientific Sessions in November.
Signals for canagliflozin, too?
SAVOR-TIMI 53 and EXAMINE provide the first results from what are more than a dozen large studies – involving more than 100,000 patients – launched recently to look for adverse cardiovascular effects from drugs in six different diabetes drug classes, according to Dr. Sanjay Kaul, who also spoke at EASD. He presented results from a meta-analysis he performed on results from nine phase III and phase II trials of canagliflozin (Invokana), an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class and approved by the FDA last March for treatment of type 2 diabetes, the first drug in that class to get U.S. marketing approval.
In the largest of these trials, CANVAS – the cardiovascular-assessment study for canagliflozin set up by the drug’s developer, Janssen – treatment with canagliflozin linked with a statistically significant, sixfold increase in cardiovascular events during the first 30 days of treatment, a link that then disappeared with longer-term treatment in patients with high CV risk. (Complete results from CANVAS have not yet been reported.) But Dr. Kaul did not see a similar excess in the other eight studies.
The canagliflozin meta-analysis also showed a nonsignificant, 46% increased risk of stroke in patients on the drug, a signal not seen in any other individual cardiovascular endpoint. Dr. Kaul analyzed data from 14 phase II and III trials for a second SGLT2 inhibitor drug, dapagliflozin, which showed no suggestion of causing any cardiovascular risk.
The canagliflozin risk signals are not reasons to stop using the drug or to withdraw it from the market, said Dr. Kaul, a member of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee. The early signal of risk in CANVAS was not seen in any other study, and it may have been a statistical artifact, he said.
He said that signals of risk must be considered relative to a drug’s benefit. Applying the same standard of cardiovascular harm to drugs that are highly effective and to drugs that are not very effective "doesn’t make sense," he said. "A risk-benefit trade-off depends on the benefit. If you have a diabetes drug that lowers hemoglobin A1c by 1.5%-2% I’m willing to accept greater harm than I would from a drug that produced a 0.5% drop in hemoglobin A1c."
A final rosiglitazone thought
Dr. Kaul also made this observation about the rosiglitazone experience, which in retrospect produced "insufficient evidence to either incriminate or exonerate rosiglitazone," he said.
"That a diabetes drug [rosiglitazone] could have become a blockbuster without any established outcome benefits does not reflect well on the drug development and approval process. Equally lamentable is that this drug was virtually killed based on insufficient evidence and entrenched opinions."
Dr. Bhatt has received research grants from several companies, including AstraZeneca and Bristol-Myers Squibb (BMS), which market saxagliptin, and Takeda, maker of alogliptin. Dr. White is a safety consultant for several companies, including AstraZeneca and Takeda. Dr. Sattar is a consultant to several pharmaceutical firms, including AstraZeneca and BMS. Dr. Kaul is a consultant to Novo Nordisk, Sanofi, and Boehringer Ingelheim, and owns stock in Johnson & Johnson.
On Twitter @mitchelzoler