Diabetes affects an estimated 30 million people in the United States  and 415 million individuals globally , most commonly type 2 diabetes (T2D) (90–95% of cases ). T2D is frequently associated with conditions such as hypertension, chronic kidney disease and heart failure [3–5], which are often treated with drugs that interrupt the renin–angiotensin system (RAS), including angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs).
Consequently, as a result of the epidemic of T2D and its associated comorbidities, a large number of individuals currently receive concomitant treatment with RAS blockers such as ACE inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors, a class of frequently prescribed oral glucose-lowering drugs . DPP-4 inhibitors reduce blood glucose levels mainly by inhibiting enzymatic degradation of glucagon-like peptide-1, a major substrate of DPP-4 that stimulates glucose-dependent insulin secretion. However, DPP-4 also has other peptide substrates, some of which are vasoactive such as substance P. Furthermore, DPP-4 is largely responsible for the inactivation of substance P when ACE is inhibited [7,8].
An adverse hemodynamic interaction between DPP-4 inhibitors and ACE inhibitors has been postulated based on pharmacological studies in which increases in blood pressure (BP) and heart rate (HR) manifested during concomitant treatment with ACE inhibitors and experimental (P32/98) or licensed DPP-4 inhibitors (sitagliptin) [9,10]. The need for further studies in this area was highlighted recently . Furthermore, there appears to be little data on potential hemodynamic interactions between DPP-4 inhibitors and ARBs. Consequently, we explored the potential hemodynamic effects of another licensed DPP-4 inhibitor, linagliptin, in individuals with T2D and renal disease as reflected by the presence of microalbuminuria or macroalbuminuria who were receiving concomitant treatment with ACE inhibitors or ARBs.
This was a prespecified, exploratory analysis of a 24-week, randomized, double-blind, placebo-controlled, multinational clinical trial of linagliptin conducted in individuals with T2D and renal dysfunction (MARLINA-T2D; ClinicalTrials.gov: NCT01792518).
MARLINA-T2D was designed to investigate the glycemic and albuminuric effects of linagliptin; the full study methodology and main results are described in detail elsewhere [12,13]. In brief, individuals with T2Ds were eligible to participate if they were aged 18–80 years with glycated hemoglobin A1c levels of 6.5–10.0%, BMI of 40 kg/m2 or less, estimated glomerular filtration rate (eGFR) at least 30 ml/min per 1.73 m2, and were either drug-naïve or receiving up to two oral glucose-lowering drugs and/or basal insulin. Individuals were also required to have albuminuria, manifesting as urinary albumin-to-creatinine ratio (UACR) of 30–3000 mg/g, or albuminuria more than 30 mg/l of urine, or urinary albumin excretion rate more than 30 μg/min clearly documented in the previous 12 months or detected at screening. Albuminuria had to be confirmed prior to randomization with a geometric mean UACR of 30–3000 mg/g from three consecutive morning urine samples collected 14–16 days before randomization. Eligible individuals must also have been receiving a stable (unchanged) dose of an ACE inhibitor or ARB for at least the ten preceding weeks.
Following a two-week placebo run-in period, participants were randomized to receive double-blind, once-daily oral treatment with linagliptin 5 mg or placebo for 24 weeks. In an exploratory analysis, changes from baseline in mean 24-h SBP, mean 24-h DBP, and mean 24-h HR – all recorded using ambulatory BP monitoring (ABPM) – were assessed at baseline and after 24 weeks of treatment. These endpoints were analyzed in the treated set of participants (those who received at least one dose of study drug) using an analysis of covariance. ABPM values measured after the start of glycemic rescue therapy or after a change in antihypertensive treatment were not included in the analysis. Post-hoc analyses were conducted for changes in ethnic subgroups (Asian/non-Asian) and changes in the day or night separately; for the latter, day and night were defined as 0601–2159 h and 2200–0600 h, respectively.
Safety analyses were performed as previously described . Adverse events of relevance to the current analysis were defined as those in the vascular disorders system organ class from the Medical Dictionary for Regulatory Activities (MedDRA) version 18.1, as well as hypersensitivity reactions (MedDRA 18.1 Standardized MedDRA Query), and cardiovascular events adjudicated by a blinded, external clinical event committee.
Of the 360 participants in the treated set, ABPM data were available at baseline for 298 individuals (linagliptin: n = 155; placebo: n = 143). At baseline, mean ± SD 24-h SBP, 24-h DBP, and 24-h HR were 132.7 ± 12.9 mmHg, 75.9 ± 9.1 mmHg and 77.3 ± 10.4 bpm, respectively (Table 1). These and other mean baseline characteristics were similar in the 208 participants (linagliptin: n = 111; placebo: n = 97) with ABPM data at both baseline and week 24 (Table 1).
At week 24, there were no significant placebo-adjusted changes from baseline in mean 24-h SBP, 24-h DBP, or 24-h HR in individuals treated with linagliptin (Fig. 1). There was no significant difference between the predominant ethnic group (Asians) and other (non-Asian) participants in these parameters: P values for treatment interaction with race were 0.7035, 0.8149, and 0.4196 for mean change from baseline in 24-h SBP, 24-h DBP, and 24-h HR respectively (Fig. S1, Supplemental Digital Content, http://links.lww.com/HJH/B54). There was also no significant treatment difference in changes in mean 24-h SBP, 24-h DBP, or 24-h HR within the day or night periods separately (Fig. S2, Supplemental Digital Content, http://links.lww.com/HJH/B54).
Background antihypertensive medication was unchanged throughout the study in the large majority of participants: only 7.2 and 5.7% of the linagliptin and placebo groups, respectively, had a change in dose, and only 9.4 and 8.6%, respectively, started a new antihypertensive medication.
In subgroups based on the type of RAS blocker received, the placebo-adjusted change from baseline in mean 24-h SBP at week 24 with linagliptin was −2.30 mmHg [95% confidence interval (CI) −7.43, 2.84; P = 0.3789] in participants receiving ACE inhibitors and 0.90 mmHg (95% CI −2.32, 4.11; P = 0.5825) in those receiving ARBs (Fig. 2). For mean 24-h DBP, the placebo-adjusted change from baseline at week 24 was −0.61 mmHg (95% CI −3.41, 2.20; P = 0.6712) in participants taking ACE inhibitors and 0.20 mmHg (95% CI −1.57, 1.96; P = 0.8260) in those taking ARBs (Fig. 2). The placebo-adjusted change from baseline in mean 24-h HR at week 24 was −0.46 bpm (95% CI −3.16, 2.24; P = 0.738) in participants receiving ACE inhibitors and 1.29 bpm (95% CI −0.40, 2.98; P = 0.135) in those receiving ARBs (Fig. 2).
The overall incidence of adverse events was similar between the linagliptin and placebo groups, with few participants experiencing vascular disorders, hypersensitivity reactions or cardiovascular events (Table 2).
In this prespecified exploratory analysis of the MARLINA-T2D study, treatment with the DPP-4 inhibitor linagliptin added to stable doses of ACE inhibitors or ARBs was not associated with changes in BP or HR in individuals with T2D and albuminuria.
A potential adverse hemodynamic interaction between DPP-4 inhibitors and ACE inhibitors was initially reported from pharmacological studies [9,10]. In the spontaneously hypertensive rat model, acute administration of an experimental DPP-4 inhibitor (P32/28) increased BP in animals pretreated with the ACE inhibitor captopril . Conversely, in a randomized, placebo-controlled, cross-over study in 24 individuals with metabolic syndrome who were pretreated for 5 days with sitagliptin, a licensed DPP-4 inhibitor, the hypotensive response to an acute high dose (10 mg) of enalapril was attenuated, but not to a low dose (5 mg) of enalapril. Sitagliptin treatment alone led to a mild hypotensive response. Furthermore, only high-dose enalapril increased HR and plasma norepinephrine concentration . The authors suggested that the mild hypotensive response to DPP-4 inhibition might be mediated in part by the attenuation of substance P metabolism. They further suggested that during combined high-dose ACE inhibition and DPP-4 inhibition, activation of the sympathetic nervous system by substance P and decreased degradation of neuropeptide Y (NPY)1–36 may offset the decreased degradation of vasodilatory peptides . The vasodilatory substance P is normally inactivated via proteolytic cleavage by ACE in vivo – however, in the absence of ACE activity, substance P is inactivated by DPP-4 [7,8]. Subsequently, the same group reported that exogenous substance P increased sympathetic activity during acute treatment with both enalapril and sitagliptin in a randomized, double-blind, placebo-controlled, cross-over study in 12 healthy individuals . The vasoconstrictive NPY1–36 is inactivated to NPY3–36 by DPP-4. In a study in the spontaneously hypertensive rat model, sitagliptin had prohypertensive effects that were mediated by NPY1–36, and the latter was shown to elicit potent vasoconstriction in the kidneys .
There are several possible reasons for the divergent findings between these previous studies and our observations on the hemodynamic effects of combined DPP-4 and ACE inhibition. First, the previous studies only investigated the acute or short-term treatment effect, whereas individuals in the MARLINA-T2D study were treated with the combination of linagliptin and either an ACE inhibitor or ARB for 24 weeks. It is unclear whether transient initial increases in BP and HR arising from combined DPP-4 and ACE inhibition would have clinical relevance in the absence of long-term changes. Second, unlike the previous studies, many participants in MARLINA-T2D were receiving other antihypertensive agents as well as ACE inhibitors, which may have attenuated increases in BP and HR. For example, one-quarter of participants were receiving β-blockers. The antihypertensive polypharmacy seen in MARLINA-T2D is common in clinical practice, as most individuals with hypertension require two or more drugs to achieve target BP, thus highlighting the clinical generalizability of these findings [16,17]. Third, the increases in BP and HR observed previously during acute treatment with sitagliptin and enalapril occurred only with high doses of the latter agent  whereas individuals in our study were treated with lower, practice-based, ACE inhibitor doses. Fourth, there may be within-class heterogeneity for interactions between ACE inhibitors and DPP-4 inhibitors, as the latter comprise a chemically diverse class of compounds whose pharmacokinetic properties vary substantially . Whereas the previous studies employed an experimental DPP-4 inhibitor, P32/98 , and a widely prescribed member of this drug class, sitagliptin , we evaluated another licensed DPP-4 inhibitor, linagliptin, with a different chemical structure. Furthermore, a recent post-hoc analysis of the EXAMINE cardiovascular outcomes study found no increase in cardiovascular events in individuals receiving combination treatment with alogliptin, another licensed DPP-4 inhibitor, and ACE inhibitors . Alogliptin treatment was also not associated with increased HR or BP as assessed rather crudely by spot measurements. Mitigating against the possibility of heterogeneity in DPP-4 inhibitor interactions with ACE inhibitors, however, is the fact that all licensed compounds including sitagliptin, linagliptin and alogliptin have high affinity for DPP-4, with half-maximal inhibitory concentration values in the low nanomolar range .
The findings of this clinical trial are consistent with preclinical studies analyzing the combination of an ARB (telmisartan) and linagliptin in a hypertensive diabetic mouse model  and in the 2-kidney 1-clip rat model of renovascular hypertension . Both studies showed that the BP-lowering effect of telmisartan was not affected by concomitant treatment with linagliptin [21,22].
Limitations of this study include the fact that treatment effects were not evaluated in subgroups based on BMI or eGFR level, due to low patient numbers in certain of these subgroups.
In conclusion, this prespecified exploratory analysis of the MARLINA-T2D clinical trial does not support the existence of an adverse hemodynamic interaction between DPP-4 inhibitors, in general, and ACE inhibitors or ARBs. The lack of an increase in BP or HR observed in our study suggests that concomitant use of linagliptin with either ACE inhibitors or ARBs in patients with albuminuric diabetic kidney disease is safe in this regard. Taken together with the lack of an increase in cardiovascular events seen in participants receiving alogliptin and ACE inhibitors in the EXAMINE study , our findings suggest that hemodynamic effects arising from the combination of a DPP-4 inhibitor and an ACE inhibitor are either limited to the acute setting or are not a class effect of DPP-4 inhibitors.
The authors thank the participants and staff involved in this study. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Giles Brooke, PhD, CMPP, of Envision Scientific Solutions during the preparation of this article.
Data from this study have previously been presented at the 52nd Annual Meeting of the European Association for the Study of Diabetes, Munich, Germany, 12–16 September, 2016.
The current study was supported by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance.
Conflicts of interest
M.E.C., V.P., P.-H.G., and B.H. have received fees for advisory services to Boehringer Ingelheim. U.H., T.M., A.K.-W., S.v.d.W., and M.v.E. are employees of Boehringer Ingelheim.
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