Angiotensin-Converting Enzyme Inhibitor Use and Major Cardiovascular Outcomes in Type 2 Diabetes Mellitus Treated With the Dipeptidyl Peptidase 4 Inhibitor Alogliptin

White WB, Wilson CA, Bakris GL, et al.
Hypertension.2016;68: published online ahead of print

Background

The co-administration of dipeptidyl peptidase 4 (DPP-4) inhibitors and angiotensin-converting enzyme (ACE) inhibitors may lead to sympathetic tone stimulation and to increased cardiovascular (CV) adverse events due to adverse haemodynamic effects [1-4].
Alogliptin is a selective DPP-4 inhibitor for the treatment of patients with type 2 diabetes mellitus (T2DM) that was not inferior to placebo in terms of CV safety in T2DM patients at high CV risk [5-7]. This analysis of the EXAMINE study looks into the clinical outcome of the combination of ACE inhibition and DPP-4 inhibition with alogliptin, by comparing the CV outcomes in patients receiving ACE inhibitors at baseline, between those receiving alogliptin vs. placebo.

Main results

• In patients not using an ACE inhibitor, there was a small, but significant reduction in systolic BP for alogliptin vs. placebo: −1.3 mm Hg (95% CI: −2.6 to −0.1; P=0.033).

• The composite rates of the primary end point (CV death, non-fatal MI, and non-fatal stroke) were comparable for alogliptin and placebo in the ACE inhibitor subgroup (11.4% vs. 11.8%; HR: 0.97; 95% CI: 0.79–1.19) and the non-ACE inhibitor subgroup (11.2% vs. 11.9%; HR: 0.94; 95% CI: 0.72–1.21).
• The composite rates for CV death and hospitalisation for heart failure (HHF) in patients on ACE inhibitors were similar for alogliptin and placebo (6.8% vs. 7.2%; HR: 0.93; 95% CI: 0.72–1.20).
• Based on the history of HF at the time of randomisation and ACE inhibitor use at baseline, the primary composite endpoint occurred in 13.9% and 16.5% of patients on alogliptin vs. placebo, respectively (HR: 0.87; 95% CI: 0.63–1.19).
• The composite of CV death and HHF occurred in 12.0% and 13.2% of patients on alogliptin vs. placebo, respectively (HR: 1.02; 95% CI: 0.72–1.44).

Conclusion

T2DM patients on ACE inhibitor therapy at high CV risk had similar outcomes when receiving the DPP-4 inhibitor alogliptin compared with placebo. The present data do not support an unfavourable interaction between ACE inhibitor use and alogliptin in these patients.

Editorial comment [8]

Wilson and Brown note in their editorial: ‘The authors are to be commended for undertaking this analysis, although there are limitations to such a post hoc analysis with respect to blood pressure. ACE inhibitor use was not randomized or consistent throughout the study. Blood pressure was not a prespecified primary end point and was measured according to standard clinical guidelines. Not surprisingly, given that ≈85% of patients were taking a β-blocker at randomization, the investigators found no effect of alogliptin on heart rate in ACE inhibitor users. Catecholamine concentrations were not measured. There was, however, an interesting signal with respect to blood pressure. In nonusers of ACE inhibitors, alogliptin reduced systolic blood pressure compared with placebo (−1.3 mm Hg; 95% CI, −2.6 to −0.1 mm Hg; P=0.033). This effect was not seen in ACE inhibitor users. This is compatible with the studies of Jackson et al, as well as human observations that sitagliptin alone reduces vascular resistance but not during concurrent ACE inhibition.’
And they conclude: ‘In short, the analysis by White et al provides reassurance that the combined use of an ACE inhibitor and DPP4 inhibitor does not increase the risk of heart failure in patients who have had an acute coronary event and are taking β-blockers. Additional mechanistic studies are needed to address whether concurrent DPP4 inhibition alters the hemodynamic responses to commonly prescribed antihypertensive agents.’

Find this article online at Hypertension

References

1. Jackson EK, Dubinion JH, Mi Z. Effects of dipeptidyl peptidase iv inhibition on arterial blood pressure. Clin Exp Pharmacol Physiol. 2008;35:29–34.
2. Marney A, Kunchakarra S, Byrne L, et al. Interactive hemodynamic effects of dipeptidyl peptidase-IV inhibition and angiotensin-converting enzyme inhibition in humans. Hypertension. 2010;56:728–733.
3. Devin JK, Pretorius M, Nian H, et al. Substance P increases sympathetic activity during combined angiotensin converting enzyme and dipeptidyl peptidase-4 inhibition. Hypertension. 2014;63:951–957.
4. Brown NJ. Cardiovascular effects of antidiabetic agents: focus on blood pressure effects of incretin-based therapies. J Am Soc Hypertens. 2012;6:163–168.
5. Keating GM. Alogliptin: a review of its use in patients with type 2 diabetes mellitus. Drugs. 2015;75:777–796.
6. White WB, Bakris GL, Bergenstal RM, et al. EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome (EXAMINE): a cardiovascular safety study of the dipeptidyl peptidase 4 inhibitor alogliptin in patients with type 2 diabetes with acute coronary syndrome. Am Heart J. 2011;162:620–626.e1.
7. White WB, Cannon CP, Heller SR, et al; EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327–1335.
8. Wilson JR, Brown NJ. Examining EXAMINE for an Interaction With Angiotensin-Converting Enzyme Inhibition. Hypertension. 2016;68:published online ahead of print.