DPP-4 Inhibitors for Diabetes May Cut Cardiovascular Risk

LOS ANGELES – The distinct possibility that using dipeptidyl peptidase-4 inhibitors to treat hyperglycemia in type 2 diabetic patients may substantially reduce the risk of major cardiovascular events has been raised in a comprehensive new meta-analysis of randomized controlled trials.

This finding must be viewed as hypothesis generating and nondefinitive in light of the well-known limitations of meta-analysis as applied to numerous small randomized trials, Dr. Kari A.O. Tikkinen cautioned at the annual scientific sessions of the American Heart Association.

"These results are encouraging, but large-scale confirmatory studies are needed before these drugs can be prescribed to lower the risk of cardiovascular events," said Dr. Tikkinen of McMaster University, Hamilton, Ontario.

Definitive answers as to whether the dipeptidyl peptidase-4 (DPP-4) inhibitors protect patients with type 2 diabetes against MI and other major adverse cardiovascular events must await the outcome of four ongoing large prospective randomized trials due to report results in 2-4 years.

Nevertheless, in the interim, the new meta-analysis provides a high degree of reassurance on one score: "We think it’s extremely unlikely that these drugs increase cardiovascular events," he declared.

Several prior meta-analyses by other investigators have been published. All had significant methodologic shortcomings, including inappropriate inclusion of "soft" cardiovascular end points and lack of grading of the quality of the evidence. This was the impetus for the new meta-analysis, which was restricted to randomized trials of at least 12 weeks’ duration in which a DPP-4 inhibitor was compared to placebo, usual care, or other active agents, most often metformin.

All trials included in the new meta-analysis showed evidence of a concerted effort by investigators to systematically capture cardiovascular events. That’s important because scrupulous attention to cardiovascular events did not always occur in studies completed prior to 2008, when the FDA issued an edict emphasizing the necessity of doing so in reaction to the unexpected finding that rosiglitazone increased cardiovascular risk, Dr. Tikkinen explained.

In the new meta-analysis, methodologically trained reviewers searched Medline, the Cochrane Library, EMBASE, and the Food and Drug Administration and European regulatory databases. They identified 42 randomized trials of DDP-4 inhibitors and 13 trials of glucagon-like peptide-1 (GLP-1) agonists that qualified. Dr. Tikkinen restricted his comments to the meta-analysis of the DPP-4 inhibitor trials; the GLP-1 agonist meta-analysis will be presented at a later date.

Nineteen DPP-4 inhibitor trials involved sitagliptin, 10 involved saxagliptin, 7 vildagliptin, and 6 alogliptin. Follow-up was 12-104 weeks, with 10 of the 42 trials featuring follow-up times in excess of 26 weeks. Nineteen trials focused on DPP-4 inhibitor monotherapy; the other 23 addressed the drugs as add-on therapy.

The primary composite end point chosen for the meta-analysis was comprised of cardiovascular death, MI, and stroke. One hundred ten of these events occurred in 24,215 randomized patients. The bottom line: The relative risk was reduced by 49% in patients on a DPP-4 inhibitor. Most of this benefit was the result of a 72% relative risk reduction in MIs in DPP-4 inhibitor-treated patients.

Patients randomized to a DPP-4 inhibitor as monotherapy had only a modest, nonsignificant reduction in the primary end point rate. In contrast, patients on add-on DPP-4 inhibitor therapy had a 54% relative risk reduction (P = .049).

"Our results suggest that add-on therapy would be more effective. However, this is borderline statistically significant and a subgroup analysis, so you should be very cautious in interpreting it," according to Dr. Tikkinen.

No difference in treatment effect was found between study durations of 12-26 weeks and more than 26 weeks. And there was no significant difference in cardioprotective efficacy between the four DPP-4 inhibitors.

"The confidence intervals overlapped, so we can’t say from our study which of these drugs is the best," he said.

Using statistical analytic methods, the investigators determined that 39 of the 42 clinical trials included in their study had a low risk of bias.

The DPP-4 inhibitors decrease blood glucose levels by enhancing activity of the incretins glucose-dependent insulinotropic peptide and glucagon-like peptide-1.

The meta-analysis was funded by Bristol-Myers Squibb and AstraZeneca. Dr. Tikkinen reported having no financial conflicts.

LOS ANGELES – The distinct possibility that using dipeptidyl peptidase-4 inhibitors to treat hyperglycemia in type 2 diabetic patients may substantially reduce the risk of major cardiovascular events has been raised in a comprehensive new meta-analysis of randomized controlled trials.

This finding must be viewed as hypothesis generating and nondefinitive in light of the well-known limitations of meta-analysis as applied to numerous small randomized trials, Dr. Kari A.O. Tikkinen cautioned at the annual scientific sessions of the American Heart Association.

"These results are encouraging, but large-scale confirmatory studies are needed before these drugs can be prescribed to lower the risk of cardiovascular events," said Dr. Tikkinen of McMaster University, Hamilton, Ontario.

Definitive answers as to whether the dipeptidyl peptidase-4 (DPP-4) inhibitors protect patients with type 2 diabetes against MI and other major adverse cardiovascular events must await the outcome of four ongoing large prospective randomized trials due to report results in 2-4 years.

Nevertheless, in the interim, the new meta-analysis provides a high degree of reassurance on one score: "We think it’s extremely unlikely that these drugs increase cardiovascular events," he declared.

Several prior meta-analyses by other investigators have been published. All had significant methodologic shortcomings, including inappropriate inclusion of "soft" cardiovascular end points and lack of grading of the quality of the evidence. This was the impetus for the new meta-analysis, which was restricted to randomized trials of at least 12 weeks’ duration in which a DPP-4 inhibitor was compared to placebo, usual care, or other active agents, most often metformin.

All trials included in the new meta-analysis showed evidence of a concerted effort by investigators to systematically capture cardiovascular events. That’s important because scrupulous attention to cardiovascular events did not always occur in studies completed prior to 2008, when the FDA issued an edict emphasizing the necessity of doing so in reaction to the unexpected finding that rosiglitazone increased cardiovascular risk, Dr. Tikkinen explained.

In the new meta-analysis, methodologically trained reviewers searched Medline, the Cochrane Library, EMBASE, and the Food and Drug Administration and European regulatory databases. They identified 42 randomized trials of DDP-4 inhibitors and 13 trials of glucagon-like peptide-1 (GLP-1) agonists that qualified. Dr. Tikkinen restricted his comments to the meta-analysis of the DPP-4 inhibitor trials; the GLP-1 agonist meta-analysis will be presented at a later date.

Nineteen DPP-4 inhibitor trials involved sitagliptin, 10 involved saxagliptin, 7 vildagliptin, and 6 alogliptin. Follow-up was 12-104 weeks, with 10 of the 42 trials featuring follow-up times in excess of 26 weeks. Nineteen trials focused on DPP-4 inhibitor monotherapy; the other 23 addressed the drugs as add-on therapy.

The primary composite end point chosen for the meta-analysis was comprised of cardiovascular death, MI, and stroke. One hundred ten of these events occurred in 24,215 randomized patients. The bottom line: The relative risk was reduced by 49% in patients on a DPP-4 inhibitor. Most of this benefit was the result of a 72% relative risk reduction in MIs in DPP-4 inhibitor-treated patients.

Patients randomized to a DPP-4 inhibitor as monotherapy had only a modest, nonsignificant reduction in the primary end point rate. In contrast, patients on add-on DPP-4 inhibitor therapy had a 54% relative risk reduction (P = .049).

"Our results suggest that add-on therapy would be more effective. However, this is borderline statistically significant and a subgroup analysis, so you should be very cautious in interpreting it," according to Dr. Tikkinen.

No difference in treatment effect was found between study durations of 12-26 weeks and more than 26 weeks. And there was no significant difference in cardioprotective efficacy between the four DPP-4 inhibitors.

"The confidence intervals overlapped, so we can’t say from our study which of these drugs is the best," he said.

Using statistical analytic methods, the investigators determined that 39 of the 42 clinical trials included in their study had a low risk of bias.

The DPP-4 inhibitors decrease blood glucose levels by enhancing activity of the incretins glucose-dependent insulinotropic peptide and glucagon-like peptide-1.

The meta-analysis was funded by Bristol-Myers Squibb and AstraZeneca. Dr. Tikkinen reported having no financial conflicts.

LOS ANGELES – The distinct possibility that using dipeptidyl peptidase-4 inhibitors to treat hyperglycemia in type 2 diabetic patients may substantially reduce the risk of major cardiovascular events has been raised in a comprehensive new meta-analysis of randomized controlled trials.

This finding must be viewed as hypothesis generating and nondefinitive in light of the well-known limitations of meta-analysis as applied to numerous small randomized trials, Dr. Kari A.O. Tikkinen cautioned at the annual scientific sessions of the American Heart Association.

"These results are encouraging, but large-scale confirmatory studies are needed before these drugs can be prescribed to lower the risk of cardiovascular events," said Dr. Tikkinen of McMaster University, Hamilton, Ontario.

Definitive answers as to whether the dipeptidyl peptidase-4 (DPP-4) inhibitors protect patients with type 2 diabetes against MI and other major adverse cardiovascular events must await the outcome of four ongoing large prospective randomized trials due to report results in 2-4 years.

Nevertheless, in the interim, the new meta-analysis provides a high degree of reassurance on one score: "We think it’s extremely unlikely that these drugs increase cardiovascular events," he declared.

Several prior meta-analyses by other investigators have been published. All had significant methodologic shortcomings, including inappropriate inclusion of "soft" cardiovascular end points and lack of grading of the quality of the evidence. This was the impetus for the new meta-analysis, which was restricted to randomized trials of at least 12 weeks’ duration in which a DPP-4 inhibitor was compared to placebo, usual care, or other active agents, most often metformin.

All trials included in the new meta-analysis showed evidence of a concerted effort by investigators to systematically capture cardiovascular events. That’s important because scrupulous attention to cardiovascular events did not always occur in studies completed prior to 2008, when the FDA issued an edict emphasizing the necessity of doing so in reaction to the unexpected finding that rosiglitazone increased cardiovascular risk, Dr. Tikkinen explained.

In the new meta-analysis, methodologically trained reviewers searched Medline, the Cochrane Library, EMBASE, and the Food and Drug Administration and European regulatory databases. They identified 42 randomized trials of DDP-4 inhibitors and 13 trials of glucagon-like peptide-1 (GLP-1) agonists that qualified. Dr. Tikkinen restricted his comments to the meta-analysis of the DPP-4 inhibitor trials; the GLP-1 agonist meta-analysis will be presented at a later date.

Nineteen DPP-4 inhibitor trials involved sitagliptin, 10 involved saxagliptin, 7 vildagliptin, and 6 alogliptin. Follow-up was 12-104 weeks, with 10 of the 42 trials featuring follow-up times in excess of 26 weeks. Nineteen trials focused on DPP-4 inhibitor monotherapy; the other 23 addressed the drugs as add-on therapy.

The primary composite end point chosen for the meta-analysis was comprised of cardiovascular death, MI, and stroke. One hundred ten of these events occurred in 24,215 randomized patients. The bottom line: The relative risk was reduced by 49% in patients on a DPP-4 inhibitor. Most of this benefit was the result of a 72% relative risk reduction in MIs in DPP-4 inhibitor-treated patients.

Patients randomized to a DPP-4 inhibitor as monotherapy had only a modest, nonsignificant reduction in the primary end point rate. In contrast, patients on add-on DPP-4 inhibitor therapy had a 54% relative risk reduction (P = .049).

"Our results suggest that add-on therapy would be more effective. However, this is borderline statistically significant and a subgroup analysis, so you should be very cautious in interpreting it," according to Dr. Tikkinen.

No difference in treatment effect was found between study durations of 12-26 weeks and more than 26 weeks. And there was no significant difference in cardioprotective efficacy between the four DPP-4 inhibitors.

"The confidence intervals overlapped, so we can’t say from our study which of these drugs is the best," he said.

Using statistical analytic methods, the investigators determined that 39 of the 42 clinical trials included in their study had a low risk of bias.

The DPP-4 inhibitors decrease blood glucose levels by enhancing activity of the incretins glucose-dependent insulinotropic peptide and glucagon-like peptide-1.

The meta-analysis was funded by Bristol-Myers Squibb and AstraZeneca. Dr. Tikkinen reported having no financial conflicts.