EXAMINING EXAMINE FOR AN INTERACTION WITH ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITION

Incretin-based therapies for type 2 diabetes mellitus (T2DM) increase glucose-dependent insulin secretion, reducing the risk of fasting hypoglycemia, and suppress glucagon secretion. Whereas stable glucagon-like peptide (GLP)-1 analogs require injection, dipeptidyl peptidase 4 (DPP4) inhibitors are orally bioavailable. DPP4 inhibitor use has grown rapidly in the United States since sitagliptin was approved in 2006. In April 2016, however, the Food and Drug Administration (FDA) added warnings to the labels of saxagliptin and alogliptin indicating that these DPP4 inhibitors may increase the risk of heart failure.

The FDA warnings resulted from a review of three major randomized, placebo-controlled clinical trials investigating the cardiovascular effects of DPP4 inhibitors that yielded disparate results with respect to the association between DPP4 inhibitor use and risk of heart failure. The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus Thrombolysis in Mycoardial Infarction (SAVOR-TIMI) 53 trial enrolled 16,492 patients with a history of cardiovascular disease or risk factors for cardiovascular disease.(1) There were no differences between the saxagliptin and placebo groups in the primary combined end point of cardiovascular death, myocardial infarction, or ischemic stroke or the major secondary combined end point of cardiovascular death, myocardial infarction, ischemic stroke, hospitalization for unstable angina, coronary revascularization, or heart failure. Unexpectedly, however, saxagliptin was associated with a significantly increased risk of hospitalization for heart failure compared to placebo (HR 1.27; 95% CI, 1.07 to 1.51; P=0.007).(1)

The Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial enrolled 5,380 patients with T2DM and a recent acute coronary event; there was no effect of drug on the primary composite endpoint of cardiovascular death, myocardial infarction and stroke.(2) Subsequently, the investigators reported a prespecified analysis of an extended composite endpoint of all-cause mortality, myocardial infarction, stroke, urgent revascularization due to unstable angina, and hospital admission for heart failure.(3) In their post-hoc analysis, there was not a statistically significant difference in admissions for heart failure in patients as a whole (HR 1.19; 95% CI, 0.90–1.58), but there was a significantly increased risk of developing heart failure in patients without a prior history of heart failure randomized to alogliptin (HR 1.76; 95% CI, 1.07–2.90).(3)

The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) enrolled patients with T2DM and established heart disease who were at least 50 years old, and had a hemoglobin A1c of 6.5 to 8.0%.(4) There was no difference in rates of hospitalization for heart failure in those treated with sitagliptin or placebo (HR 1.00; 95% CI, 0.83–1.20). Patients in the placebo group were more likely to be initiated on additional oral antihyperglycemic agents (p<0.001) and insulin (p<0.001) than those in the sitagliptin group.(4) This differed from EXAMINE and SAVOR-TIMI 53, in which the use of additional antihyperglycemic agents was overall similar in the DPP4 inhibitor and placebo groups (higher insulin use in the placebo group of SAVOR-TIMI 53 was not until 2-year follow up). Differences in concurrent medication use could contribute to differences in observed effects on heart failure risk.

Dissimilar findings among these clinical trials can be hypothesized to result from drug-specific (versus class) effects, differences in clinical trial design, or variability in the response to drug due to mechanistic interactions with patient factors such as concurrent medications. In this issue of Hypertension, White et al. address the possibility of an interactive effect of DPP4 inhibition with ACE inhibition in an analysis of EXAMINE trial.(5)

Understanding the rationale for this analysis requires understanding potential mechanism(s) through which DPP4 inhibitors could exert cardiovascular effects. DPP4 is a serine exopeptidase that cleaves the amino-terminus of peptides with a penultimate proline or alanine. DPP4 inhibitors prevent the degradation of vasoactive peptides, which can have beneficial or detrimental cardiovascular effects, including: GLP-1, brain natriuretic peptide (BNP), substance P, neuropeptide Y (NPY), and peptide YY.

GLP-1 may cause vasodilation through GLP-1 receptor dependent and independent-mechanisms [the latter via degradation to GLP-1 (9–36) by DPP4], enhance endothelial function in rodents, and enhance endothelium-dependent vasodilation in humans although it has no direct vasodilatory effects.(6)(11) GLP-1 also stimulates increases in blood pressure and heart rate by activating autonomic regulatory neurons.(7) Although decreased degradation of BNP by DPP4 would be expected to cause vasodilation and natriuresis, sitagliptin does not potentiate the vasodilator response to BNP in the human forearm.(11)

NPY [NPY (1–36)] is co-released with norepinephrine during sympathetic activation and causes vasoconstriction via Y1 receptors. NPY also potentiates the action of norepinephrine and the actions of angiotensin II. DPP4 cleaves the amino terminus (Tyr-Pro) of NPY to generate NPY (3–36), which is inactive at the Y1 receptor and activates Y2 and Y5 receptors; stimulation of pre-synaptic Y2 receptors decreases the release of norepinephrine (Figure). By preventing the cleavage of NPY to NPY (3–36), DPP4 inhibitors might increase blood pressure or heart rate. Jackson et al have reported that DPP4 inhibition increases blood pressure in spontaneously hypertensive rats treated with an ACE inhibitor or hydralazine and that this effect is blocked by a Y1 receptor antagonist, consistent with a Y1-dependent effect of DPP4 inhibition on blood pressure.(8,9)

Figure.

Potential mechanisms through which dipeptidyl peptidase 4 (DPP4) inhibitors could affect blood pressure. DPP4 inhibition increases glucagon like peptide-1 (GLP-1), which may enhance endothelial-dependent vasodilation (not shown). Substance P (SP) from C fibers is inactivated by angiotensin-converting enzyme (ACE) as well as by DPP4. SP causes vasodilation, but also stimulates the release of norepinephrine (NE) and neuropeptide Y [NPY; NPY (1–36)] from sympathetic nerves via the NK1 receptor. NE increases heart rate and causes vasoconstriction. NPY is also a DPP4 substrate. NPY acts at its Y1 receptor to cause vasoconstriction and potentiate the effects of NE. In contrast, NPY (3–36), formed by DPP4, decreases NE release by sympathetic terminals via the Y2 receptor. Angiotensin II (Ang II) causes vasoconstriction and augments the effects of NE.

Among the vasoactive peptide substrates of DPP4, substance P stands out as a shared substrate with ACE. Substance P causes vasodilation and increases microvascular permeability, possibly contributing to angioedema during combined ACE and DPP4 inhibition. Substance P also acts on adrenergic nerve endings to promote norepinephrine release, which may occur with combined ACE and DPP4 inhibition due to decreased substance P degradation. Our group has reported previously that DPP4 inhibition attenuates the effect of high dose ACE inhibition, increasing heart rate and circulating catecholamines.(10) Whether DPP4 inhibition attenuates the vasodilator effect of chronic ACE inhibition or other anti-hypertensive agents has not been reported.

In a post-hoc analysis of the EXAMINE trial White et al. found no effect of alogliptin on composite rates of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke in either ACE inhibitor users or nonusers. 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 pre-specified primary endpoint and was measured according to standard clinical guidelines.

Not surprisingly, given that ~89% of patients were taking a beta 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 to placebo (−1.3 mmHg; 95% CI, −2.6 to −0.1 mmHg; p=0.003). This effect was not seen in ACE inhibitor users. This is compatible with the studies of Jackson and colleagues, as well as human observations that sitagliptin alone reduces vascular resistance but not during concurrent ACE inhibition.(8,11,12)

In short, the analysis by White 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 beta blockers. Additional mechanistic studies are needed to address whether concurrent DPP4 inhibition alters the hemodynamic responses to commonly prescribed anti-hypertensive agents.