In patients with type 2 diabetes mellitus and cardiovascular diseases, concomitant administration of the angiotensin converting enzyme (ACE) inhibitors and the dipeptidyl dipeptidase 4 (DPP-4) inhibitors is common. In the clinical pharmacology laboratory, adverse hemodynamic effects have been reported when high doses of ACE inhibitors are taken on a background of DPP-4 inhibitors.^1,2 These effects may be due to increases in substance P, a stimulator or sympathetic tone and a substrate for DPP-4.² The results of this interaction include short-term increases in heart rate and blood pressure.³ Thus, the potential for offsetting the beneficial effects of ACE inhibitors by a DPP-4 inhibitor in patients with heart disease became a concern.³ To address this issue, we had the opportunity to study this potential interaction in the EXAMINE (Exploring the Cardiovascular Safety of Therapies for Type 2 Diabetes) trial,^4,5 a large cardiovascular outcomes study, that assessed the effects of the DPP-4 inhibitor alogliptin on major cardiovascular events and in a population that had a high proportion of study participants taking an ACE inhibitor.

Patients were included in the EXAMINE trial if they had a diagnosis of type 2 diabetes requiring anti-hyperglycemic therapy and had had an acute coronary syndrome in the 15 to 90 days before being randomized to the DPP 4 inhibitor alogliptin or placebo. The majority of the 5380 patients in the study had an acute myocardial infarction (vs. unstable angina) and 62% were taking an ACE inhibitor at the time of randomization. We divided the population into those taking an ACE inhibitor (n = 3323) and those not taking an ACE inhibitor (n = 2057). Within those subgroups, there were similar characteristics for the patients randomized to aloglitpin or placebo. Of interest, patients taking ACE inhibitors were more likely to be male, had shorter durations of type 2 diabetes, had higher body mass indexes, and were less like to be Asian (the EXAMINE trial was conducted in nearly 50 different countries and 19% of the study patients came from Asia). Patients on ACE inhibitors at baseline were also more likely to have hypertension, heart failure, and preserved kidney function than those patients not taking an ACE inhibitor. Overall, nearly 85% of patients in the EXAMINE trial were taking beta-blockers, 90% were taking a statin, and 90% were taking antiplatelet therapy.

Following randomization, vital signs including heart rates measured by electrocardiography and conventional measurements of blood pressure by observers in duplicate were obtained at 1, 3, 6, 9, and 12 months during the first study year and at 4 month intervals in subsequent years. All serious cardiovascular events were prospectively adjudicated by a formal committee blinded to treatment assignment to determine the following primary and secondary events: death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, urgent revascularization for unstable angina, and hospitalization for heart failure. The rates of these events were compared for alogliptin versus placebo stratified by baseline history of ACE inhibitor use at the time of randomization using Cox proportional hazard modeling and adjusted by kidney function and region of the world. In addition, specific subgroup analyses were done according to a history of heart failure and lower versus higher doses of ACE inhibitors. Lower doses of ACE inhibitor were defined as the initial dose for the treatment of hypertension and higher doses were defined as those doses that were greater than the initial approved dose for the treatment of hypertension.

Changes in the use of antihypertensive therapies including ACE inhibitors over the course of the trial were similar in patients randomized to alogliptin and placebo. There were no significant changes from baseline in blood pressure and heart in patients taking alogliptin versus placebo when on a background of ACE inhibitor therapy. In patients not using an ACE inhibitor, there was a small, significant reduction in the systolic blood pressure on alogliptin versus placebo (-1.3 mmHg, p = 0.033).

Composite rates of the primary MACE endpoint (death from cardiovascular causes, nonfatal myocardial infarction and nonfatal stroke) were comparable in the aloglitpin and placebo groups who also took an ACE inhibitor (11.4% and 11.8%, respectively with a hazard ratio of 0.97, 95% confidence interval of 0.79-1.19) as well as those not taking an ACE inhibitor (11.2% and 11.9% for alogliptin and placebo respectively; hazard ratio of 0.94, 95% CI of 0.72-1.21) (Figure 1A). Similar results were seen for the composite of cardiovascular death or hospitalized heart failure as well as for their components (Figure 1B). Additionally, the event rates for these composites were similar for alogliptin and placebo in patients taking ACE inhibitors who had a baseline history of heart failure. Finally, no differences for alogliptin versus placebo for any event category was different according to lower versus higher doses of the ACE inhibitors.

Figure 1A
Time to First Event for Cardiovascular Death, Nonfatal MI, and Nonfatal Stroke on Alogliptin versus Placebo According to ACE inhibitor Use

Figure 1B
Time to First Event for Cardiovascular Death and Hospitalized Heart Failure on Alogliptin versus Placebo According to ACE inhibitor Use

A potential concern was raised for an untoward hemodynamic outcome when users of DPP-4 inhibitors also took an ACE inhibitor for the treatment of hypertension, heart failure or cardio-protection in the post-myocardial infarction period.^2,3 The key concern was that patients on higher doses of ACE inhibitors would have an attenuation of efficacy (less blood pressure reduction) or an increase in the heart rate mediated by substance P or the neurotransmitter neuropeptide Y.⁴ For instance, when ACE is inhibited, substance P is cleaved at its amino terminus and inactivated by DPP-4. Therefore, inhibiting both ACE and DPP-4 could theoretically stimulate the effects of the substance P. If this led to sympathetic nervous system activation, it could counteract some of the antihypertensive efficacy of an ACE inhibitor. Our data do not support this notion based on long-term measurements of blood pressure and heart rate; however, there is a remote possibility that such a finding might have been missed due to the different methodologies of data collection (fastidious frequent measurements of blood pressure and heart rate in a short-term clinical pharmacology program vs. more sparse measurements made in a large clinical outcome trial). Nevertheless, any blood pressure changes would likely be very small and of limited or no clinical importance.

In conclusion, we found no signal of an increased rate of cardiovascular events on alogliptin compared to placebo in patients treated with ACE inhibitors versus those patients not taking an ACE inhibitor. Hence, in a population of high cardiovascular risk patients taking the DPP-4 inhibitor alogliptin and standard, evidence based secondary preventive therapies, no untoward effects on ACE inhibitor benefits occurred over a median follow-up period of 18-19 months.

References

1. Marney A, Kunchakarra S, Byrne L, Brown NJ. Interactive hemodynamic effects of dipeptidyl peptidase IV inhibition and angiotensin converting enzyme inhibition in humans. Hypertension 2010;56:728-33.
2. Devin JK, Pretorius M, Nian H, Yu C, Billings FT, Brown NJ. Substance P increases sympathetic activity during combined angiotensin-converting enzyme and dipeptidyl peptidase 4 inhibition. Hypertension 2014;63:951-7.
3. Brown NJ. Cardiovascular effects of antidiabetic agents: focus on blood pressure effects of incretin based therapies. J Am Soc Hypertens 2012;6:163-8.
4. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndromes in patients with type 2 diabetes. N Engl J Med 2013;369:1327-35.
5. White WB, Wilson CA, Bakris GL, et al. Angiotensin converting enzyme inhibitor use and major cardiovascular outcomes in type 2 diabetes treated with the dipeptidyl peptidase 4 inhibitor alogliptin. Hypertension 2016;68:606-13.

Keywords: Acute Coronary Syndrome, Angina, Unstable, Angiotensin-Converting Enzyme Inhibitors, Antihypertensive Agents, Blood Pressure, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Dipeptidases, Electrocardiography, Heart Failure, Heart Rate, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertension, Myocardial Infarction, Neuropeptide Y, Neurotransmitter Agents, Peptidyl-Dipeptidase A, Pharmacology, Clinical, Risk Factors, Stroke, Uracil

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