NEW YORK (Reuters Health) – Concomitant metformin use is associated with cardiovascular outcomes of the use of dipeptidyl peptidase 4 (DPP-4) inhibitors, according to a meta-analysis of three clinical trials.
“Because the cardiovascular effects of DPP-4 inhibitors may vary based on whether they are coprescribed with metformin, there is residual uncertainty as to whether DPP-4 inhibitors are associated with cardiovascular neutrality, benefit, or harm depending on how they are used in practice,” said Dr. Matthew J. Crowley from Durham VA Medical Center and Duke University School of Medicine, in Durham, North Carolina.
“How diabetes medication classes interact to affect cardiovascular outcomes is not well understood, and this analysis highlights this important area for future research,” he told Reuters Health by email.
Dr. Crowley’s team explored metformin use as a potential moderator of the cardiovascular effects of DPP-4 inhibitors in their meta-analysis of cardiovascular outcome trials of sitagliptin, alogliptin and saxagliptin.
Overall, DPP-4 inhibitors had a neutral effect on the primary outcome, a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, the researchers report in Diabetes Care, online October 19.
Metformin users experienced a trend toward reduction in the incidence of the primary outcome with DPP-4 inhibitors, whereas nonusers showed a trend toward harm with DPP-4 inhibitors.
Meta-regression analysis showed a significant difference in the relative effects of DPP-4 inhibitors based on metformin status.
“This is an exploratory analysis, but DPP-4 inhibitors may be particularly well-suited for use in conjunction with metformin,” Dr. Crowley said. “The idea for this analysis came about because we know that part of metformin’s mechanism of action of is to enhance incretin hormone production from the intestine, while DPP-4 inhibitors inhibit the degradation of incretin hormones. Our findings support this potential synergy.”
“Our findings shouldn’t affect how DPP-4 inhibitors are used – yet,” he said. “A limitation of this exploratory analysis is that it could not account for other possible differences between metformin users and non-users in the trials we analyzed. For example, because chronic kidney disease and congestive heart failure may make providers hesitate to prescribe metformin, metformin users might have had lower rates of these conditions. If that were the case, then an alternative interpretation of our findings would be that DPP-4 inhibitors lead to better outcomes in the absence of chronic kidney disease or congestive heart failure.”
“We hope to address the issue of population differences by examining the interaction between metformin and DPP-4 inhibitors using patient-level data from these trials,” Dr. Crowley said.
“Seemingly boring ‘neutral’ effects of cardiovascular outcomes trials may hide some interesting potential of the same drugs for producing either benefits or harm,” said Dr. Michael Nauck from Ruhr-University Bochum, in Germany, who recently reviewed the cardiovascular actions of DPP-4 inhibitors.
He added that “a closer look” is needed. “It is important to identify the real factors responsible for differences between patients receiving metformin or not,” Dr. Nauck, who was not involved in the meta-analysis, told Reuters Health by email.
“Since there are many contraindications for metformin (advanced chronic kidney disease, congestive heart failure), such conditions may be the real reason for the adverse outcomes in those not receiving metformin,” he said. “Also, it is advisable to note the weak statistical significance of the present analysis (neither subgroup showed a significant effect of DPP-4 inhibitors on cardiovascular outcomes; only meta-regression analysis showed a significant p-value).”
“Thus,” Dr. Nauck concluded, “this is interesting as a hypothesis, but not definite in the sense that clinical recommendations can be founded on these results.”
Dr. Ewald Kolesnik from Medical University of Graz, Austria, who has investigated links between saxagliptin and heart failure, told Reuters Health by email, “I think DPP-4 inhibitors are a safe pharmacological treatment strategy; however, their use should be restricted to patients without severe cardiac risk factors as an individual choice for each patient (as all therapies should be applied individually).”
“Despite intensive research on DPP-4 inhibitors, the link between overwhelming beneficial results of bench-research and a more or less missing effect in clinical trials (bedside-research) is still missing,” concluded Dr. Kolesnik, who also was not involved in the study.
SOURCE: http://bit.ly/2B3dPVn
Diabetes Care 2017.
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