Effect of Dipeptidyl Peptidase-4 Inhibitors on Cardiovascular Outcome and Cardiac Function in Patients With Diabetes and Heart Failure　― Insights From the Ibaraki Cardiac Assessment Study-Heart Failure (ICAS-HF) Registry ―

Abstract

Background: Although experimental animal studies report many pleiotropic effects of dipeptidyl peptidase-4 inhibitors (DPP-4i), their prognostic value has not been demonstrated in clinical trials.

Methods and Results: Among 838 prospectively enrolled heart failure (HF) patients hospitalized for acute decompensated HF, 79 treated with DPP-4i were compared with 79 propensity score-matched non-DPP-4i diabetes mellitus (DM) patients. The primary endpoint was all-cause mortality; the secondary endpoint was a composite of cardiovascular death and hospitalization. During follow-up (423±260 days), 8 patients (10.1%) in the DPP-4i group and 13 (16.5%) in the non-DPP-4i group died (log-rank, P=0.283). The DPP-4i group did not have a significantly higher rate of all-cause mortality (log-rank, P=0.283), or cardiovascular death or hospitalization (log-rank, P=0.425). In a subgroup analysis of HF with preserved ejection fraction (HFpEF; n=75), the DPP-4i group had a significantly better prognosis than the non-DPP-4i group regarding the primary endpoint (log-rank, P=0.021) and a tendency to have better prognosis regarding the secondary endpoint (log-rank, P=0.119). In patients with HF with reduced EF (n=83), DPP-4i did not result in better prognosis.

Conclusions: DPP-4i did not increase the risk of adverse clinical outcomes in patients with DM and HF. DPP-4i may be beneficial in HFpEF.

Diabetes mellitus (DM) is one of the major comorbidities of heart failure (HF), and HF is a major cardiovascular complication of DM.¹ Patients with DM have a 2.5-fold greater risk of HF than individuals without DM.²

Dipeptidyl peptidase-4 inhibitors (DPP-4i) have recently become widely used to treat type 2 DM. Animal studies report many pleiotropic effects of DPP-4i. For example, DPP-4i have been shown to exert a cardioprotective effect on cardiovascular disease including hypertension,³ HF with reduced ejection fraction (HFrEF),⁴ HF with preserved EF (HFpEF),⁵ myocardial infarction,⁶ and cardiac hypertrophy.⁷ Therefore, DPP-4i are expected to inhibit cardiovascular events in clinical trials. The superior prognostic value of DPP-4i, however, has not been demonstrated in clinical trials such as the SAVOR-TIMI 53 trial⁸ or the EXAMINE trial.⁹ In contrast, a randomized meta-analysis of 9 studies that evaluated the effect of DPP-4i on the risk of HF in patients with type 2 DM showed that DPP-4i significantly increase the risk of HF by approximately 15%.¹⁰ The TECOS study recently showed that the DPP-4i sitagliptin does not increase the risk of major adverse cardiovascular events in patients with type 2 DM.¹¹ The effect of DPP-4i on cardiovascular outcome and cardiac function, however, especially in DM patients with HF, remains unclear.

The pathophysiology of HFpEF has been clarified in the last decade. Although a few clinical trials suggest a possible benefit of DPP-4i with regard to morbidity and clinical parameters, no treatment has been identified to provide a proven reduction in mortality.^12–14 Animal studies show that DPP-4i prevent cardiomyocyte hypertrophy and perivascular fibrosis, and improve endothelial dysfunction.^7,15 Increased left ventricular (LV) and arterial stiffness as well as endothelial dysfunction are common pathophysiological features of HFpEF.^16,17 Therefore, DPP-4i might be able to inhibit HFpEF progression. In particular, animal experiments show that DPP-4i inhibit LV hypertrophy and fibrosis, and decrease blood pressure. Therefore, DPP-4i could be more effective for improving prognosis in HFpEF, in which the increase in left atrial (LA) pressure due to LV hypertrophy is the pathological feature that distinguishes it from HFrEF. In addition, despite the few subjects available, the effect of DPP-4i on prognosis might be clarified by investigating DM patients with HF.

Accordingly, this study investigated (1) the effect of DPP-4i on cardiovascular outcome and cardiac function in patients with type 2 DM and HF; and (2) the differences in the effects of DPP-4i on HFpEF and HFrEF.

Methods

Subjects and Protocol

The subjects consisted of 838 patients who were hospitalized for acute decompensated HF and enrolled in the Ibaraki Cardiac Assessment Study-Heart Failure Registry (ICAS-HF registry). The registration period was June 2012 through March 2015. The ICAS-HF is a prospective, observational, multi-center registry pulling data from 11 institutions. The diagnosis of HF was made according to the Framingham criteria.¹⁸ The exclusion criteria were as follows: age <20 years; lack of informed consent to the attending physician; limited life expectancy owing to malignant neoplasms; inability to undergo 2 years of observation; and a judgement of medically inappropriate by the attending physician. DM was defined as requirement of stable doses of anti-hyperglycemic agents including insulin, the presence of hemoglobin A1c (HbA1c) ≥6.5% at hospitalization. Patients were divided into 2 groups on the basis of DPP-4i treatment at hospital discharge: the DPP-4i group and the non-DPP-4i group. The primary endpoint was all-cause mortality, and the secondary endpoint was a composite of cardiovascular death and hospitalization. The investigation conformed to the principles outlined in the Declaration of Helsinki. The institution ethics committee approved the protocol. Written informed consent was provided by all patients before enrolment.

Echocardiography

Echocardiography including 2-D, pulsed-wave, continuous-wave, and color Doppler imaging was performed in a stable condition before hospital discharge and after 1 year from discharge. Standard echocardiographic measurements for the evaluation of LA size and LV geometry and function were performed according to the American Society of Echocardiography guidelines.¹⁹ LVEF and LA volume were measured using the modified Simpson’s method in the apical view. Preserved ejection fraction was defined as LVEF ≥45%.²⁰

Statistical Analysis

Data are expressed as n (%) or mean±SD where appropriate. Unpaired and paired Student t-tests were conducted for normally distributed data; and data with skewed distribution were analyzed with non-parametric tests. Categoric data were compared using chi-squared or Fisher exact tests as appropriate. P<0.05 was considered to indicate statistical significance. We used the Cox proportional hazards model to analyze mortality and time-to-event endpoints. Kaplan-Meier analysis was used to determine the effects of DPP-4i on the primary and secondary endpoints. All analyses were performed with SPSS version 24 for Windows (SPSS, Chicago, IL, USA).

Propensity Score Matching

Because patients were not randomly assigned to receive DPP-4i, we matched patients according to their propensity for DPP-4i treatment. A multivariate logistic regression model (i.e., propensity model) was fitted to calculate the probability of DPP-4i treatment according to 25 of the baseline variables listed in Table 1 (age, sex, New York Heart Association [NYHA] class, systolic blood pressure, body mass index, LVEF, ischemic etiology, hypertension, atrial fibrillation, chronic obstructive pulmonary disease, smoking, B-type natriuretic peptide [BNP], Hb, sodium concentration, estimated glomerular filtration rate [eGFR], HbA1c, insulin use, sulphonylurea, biguanide, diuretics, β-blocker, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, aldosterone antagonist, and statin use). The resultant probabilities were then transformed into propensity score logits. Propensity score matching was performed for the DPP-4i and non-DPP-4i groups with 1-to-1 calliper matching using a calliper width equal to 20% of the SD of the logit of the calculated propensity score.²¹ SPSS version 24 for Windows was used for propensity score matching.

Table 1. Baseline Patient Characteristics vs. DPP-4i Treatment

Variable	Before propensity matching (n=355)			After propensity matching (n=158)
	DPP-4i (+) (n=127)	DPP-4i (−) (n=228)	P-value	DPP-4i (+) (n=79)	DPP-4i (−) (n=79)	P-value
Propensity score logit	−0.09±1.03	−0.93±0.83	<0.001	−0.47±0.86	−0.47±0.85	0.910
Sociodemographic characteristics
Age (years )	71±11	72±12	0.205	71±10	70±14	0.814
Sex (male)	78 (61.4)	154 (67.8)	0.223	49 (62.0)	46 (58.2)	0.626
Clinical characteristics
NYHA class III or IV	17 (13.4)	34 (15.0)	0.682	12 (15.2)	11 (13.9)	0.822
SBP (mmHg)	147±38	150±38	0.476	146±39	152±39	0.309
BMI (kg/m2)	23.0±4.2	23.0±4.0	0.966	23.2±3.9	23.1±4.3	0.894
LVEF (%)	45±15	44±15	0.765	45±15	45±15	0.919
Comorbidities
Ischemic etiology	59 (46.5)	101 (44.5)	0.722	36 (45.6)	33 (41.8)	0.630
Hypertension	86 (67.7)	139 (61.2)	0.224	48 (60.8)	47 (59.5)	0.871
Atrial fibrillation	31 (24.4)	75 (33.0)	0.086	22 (27.9)	23 (29.1)	0.860
COPD	9 (7.1)	13 (5.7)	0.611	4 (5.1)	6 (7.6)	0.514
Smoking	62 (48.8)	139 (61.2)	0.024	41 (51.9)	42 (53.2)	0.873
Biochemistry
BNP (pg/mL)	438±891	423±468	0.828	500±1,060	420±456	0.539
Hemoglobin (g/dL)	12.0±2.2	12.3±2.5	0.228	12.3±2.3	12.3±2.5	0.987
Sodium (mEq/L)	138±5	139±4	0.044	140±4	139±4	0.250
eGFR (mL/min/1.73 m2)	49±24	48±22	0.634	48±22	49±23	0.802
HbA1c (%)	7.2±1.0	7.0±1.1	0.138	7.1±1.0	7.2±1.2	0.677
Medication
Insulin	8 (6.3)	35 (15.4)	0.012	7 (8.9)	5 (6.3)	0.548
Sulphonylurea	33 (26.0)	27 (11.9)	<0.001	15 (19.0)	12 (15.2)	0.526
Biguanide	17 (13.4)	9 (4.0)	0.001	8 (10.1)	7 (8.9)	0.786
Pioglitazone	2 (1.6)	1 (0.4)	0.262	0 (0)	1 (1.3)	0.316
α-Glucosidase inhibitor	30 (23.6)	23 (10.1)	<0.001	15 (19.0)	10 (12.7)	0.276
Diuretics	100 (78.4)	189 (83.3)	0.296	65 (82.3)	65 (82.3)	1.000
β-blocker	95 (74.8)	172 (75.8)	0.839	62 (78.5)	60 (76.0)	0.704
ACEI/ARB	95 (74.8)	154 (67.8)	0.166	59 (74.7)	55 (69.6)	0.478
CCB				24 (30.4)	27 (34.2)	0.610
Aldosterone antagonist	72 (56.7)	142 (62.6)	0.279	51 (64.6)	49 (62.0)	0.741
Statin	67 (52.8)	96 (42.3)	0.058	39 (49.4)	35 (44.3)	0.524

Data given as mean±SD or as n (%). ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BMI, body mass index; BNP, B-type natriuretic peptide; CCB, calcium channel blocker; COPD, chronic obstructive pulmonary disease; DPP-4i, dipeptidyl peptidase-4 inhibitor; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; SBP, systolic blood pressure.

Results

Baseline Characteristics

Among the 838 patients, 41 were excluded: 13 patients had undergone hemodialysis and 28 died in hospital. Thus, the analysis included 797 patients. Among them, 442 (55.5%) did not have DM and 355 (44.5%) had DM. Patients with DM (n=355) were divided into a DPP-4i group (n=127, 35.8%) and non-DPP-4i group (n=228, 64.2%) according to DPP-4i status at discharge (Figure 1). Duration of hospitalization was not significantly different between the DPP-4i and non-DPP-4i groups (28±24 days vs. 27±22 days, P=0.478). The median follow-up period was 423±260 days, and the maximum follow-up period was 1,008 days. The prevalence and average dose of each DPP-4i were as follows: sitagliptin (n=60, 52±21 mg), vildagliptin (n=22, 80±25 mg), teneligliptin (n=11, 24±8 mg), alogliptin (n=8, 23±5 mg), linagliptin (n=2, 5±0 mg), and anagliptin (n=1, 200±0 mg).

Figure 1.

Study flow diagram. DM, diabetes mellitus; DPP-4i, dipeptidyl peptidase-4 inhibitor.

The subject baseline characteristics are listed in Table 1. Notably, the prevalence of smoking; use of insulin, sulfonylurea, or biguanide; and sodium concentration were lower in the DPP-4i group than the non-DPP-4i group. Some patients with DM were treated only with diet and exercise therapy or diagnosed for the first time at hospitalization, hence the sum of the use of all medicines does not add up to 100% in the non-DPP-4i group.

During a median follow-up of 423 days, there were 49 deaths (13.8%) and 124 cardiovascular deaths or hospitalization events (34.9%). Despite the use of DPP-4i, the rates of all-cause mortality, and cardiovascular death and hospitalization were similar between the DPP-4i and non-DPP-4i groups (Table 2; Figure 2). No hypoglycemic event during hospitalization was observed. Furthermore, there was no hypoglycemia-related hospitalization during the follow-up period.

Table 2. Impact of DPP-4i on Clinical Outcome

	Event rates			Cox proportional hazard model
	Total	DPP-4i (+)	DPP-4i (−)	HR (95% CI)	P-value
Entire cohort (n=355)
All-cause mortality	49/355 (13.8)	15/127 (11.8)	34/228 (14.9)	0.95 (0.75–1.20)	0.655
Cardiovascular death and hospitalization	124/355 (34.9)	41/127 (32.3)	83/228 (36.4)	0.91 (0.69–1.18)	0.477
Propensity-matched cohort (n=158)
All-cause mortality	21/158 (13.3)	8/79 (10.1)	13/79 (16.5)	0.89 (0.64–1.26)	0.521
Cardiovascular death and hospitalization	53/158 (33.5)	24/79 (30.4)	29/79 (36.7)	0.96 (0.65–1.41)	0.826

Abbreviations as in Table 1.

Figure 2.

Kaplan-Meier survival curves for (A) all-cause mortality and (B) composite of cardiovascular death and hospitalization in a propensity-matched cohort according to use of dipeptidyl peptidase-4 inhibitors (DPP-4i).

Propensity Score-Matched Cohort

Seventy-nine patients (62.2%) in the DPP-4i group were able to be propensity matched to the non-DPP-4i group, resulting in a propensity-matched cohort of 158 patients (79 each in the DPP-4i and non-DPP-4i groups). After matching, there was no significant difference in the mean propensity score between the matched groups (P=0.910), and the balance between the groups improved markedly, given that none of the baseline characteristics differed significantly (Table 1).

In the propensity-matched cohort, there were 21 deaths (13.3%) and 53 cardiovascular deaths or hospitalization events (33.5%) during follow-up. DPP-4i use was not associated with a statistically significant increase in the likelihood of all-cause mortality (DPP-4i, 10.1% vs. non-DPP-4i, 16.5%; hazard ratio [HR], 0.89; 95% CI: 0.64–1.26; P=0.521), or cardiovascular death or hospitalization (DPP-4i, 30.4% vs. non-DPP-4i, 36.6%; HR, 0.96; 95% CI: 0.65–1.41; P=0.826; Table 2; Figure 2).

Change in eGFR and HbA1c During Hospitalization

Significant change in eGFR between hospital admission and discharge was not observed, either before (total cohort, 48±22 to 49±23 mL/min/1.73 m², P=0.518; DPP-4i, 49±23 to 49±24 mL/min/1.73 m², P=0.804; non-DPP-4i, 48±21 to 48±23 mL/min/1.73 m², P=0.506) or after propensity matching (total cohort, 50±22 to 48±22 mL/min/1.73 m², P=0.196; DPP-4i, 50±22 to 48±22 mL/min/1.73 m², P=0.126; non-DPP-4i, 49±22 to 49±23 mL/min/1.73 m², P=0.887).

Furthermore, significant change in HbA1c during hospitalization was observed in the total cohort and DPP-4i group before propensity matching (total cohort, 7.2±1.3 to 7.1±1.1%, P=0.003; DPP-4i, 7.5±1.4 to 7.2±1.0%, P=0.014; non-DPP-4i, 7.1±1.3 to 7.0±1.1%, P= 0.078), but not after propensity matching (total cohort, 7.2±1.3 to 7.1±1.1%, P=0.176; DPP-4i, 7.2±1.0 to 7.1±1.0%, P=0.408; non-DPP-4i, 7.2±1.5 to 7.2±1.2%, P=0.277).

HFpEF and HFrEF

We performed subgroup analysis of the propensity-matched cohort according to LVEF at hospital discharge. None of the baseline characteristics significantly differed according to DPP-4i status in either the HFpEF (n=75, LVEF ≥45%) or HFrEF groups (n=83, LVEF <45%; Table 3). Kaplan-Meier estimates of the time to endpoint are shown in Figure 3. In the HFpEF patients, the DPP-4i group had significantly better prognosis than the non-DPP-4i group regarding all-cause mortality (log-rank, P=0.021) and tended to have better prognosis regarding cardiovascular death and hospitalization events (log-rank, P=0.119). In the HFrEF patients, however, the DPP-4i group did not have better prognosis regarding all-cause mortality (log-rank, P=0.403) or cardiovascular death and hospitalization events (log-rank, P=0.788).

Table 3. Baseline Patient Characteristics vs. LVEF Status

Variable	HF with reduced ejection fraction (n=83)			HF with preserved ejection fraction (n=75)
	DPP-4i (+) (n=43)	DPP-4i (−) (n=40)	P-value	DPP-4i (+) (n=36)	DPP-4i (−) (n=39)	P-value
Sociodemographic characteristics
Age (years)	69±10	67±15	0.432	72±9	73±13	0.664
Sex (male)	13 (30)	16 (40)	0.351	19 (53)	22 (56)	0.752
Clinical characteristics
NYHA class III or IV	8 (19)	7 (18)	0.900	4 (11)	4 (10)	0.905
SBP (mmHg)	139±31	143±35	0.600	153±45	161±41	0.438
BMI (kg/m2)	22.8±4.0	23.6±4.9	0.382	23.7±3.7	22.5±3.6	0.185
LVEF (%)	33±7	32±7	0.642	58±9	58±10	0.747
Comorbidities
Ischemic etiology	21 (49)	19 (48)	0.903	15 (42)	14 (36)	0.608
Hypertension	22 (51)	23 (58)	0.563	26 (72)	24 (62)	0.327
Atrial fibrillation	34 (79)	30 (75)	0.659	23 (64)	26 (65)	0.801
COPD	2 (5)	4 (10)	0.347	2 (6)	2 (5)	0.934
Smoking	23 (54)	22 (55)	0.890	18 (50)	20 (51)	0.918
Biochemistry
BNP (pg/mL)	465±474	448±501	0.872	302±326	391±410	0.301
Hemoglobin (g/dL)	13.5±2.1	13.1±2.4	0.423	12.2±2.6	11.5±2.7	0.309
Sodium (mEq/L)	139±4	139±4	0.784	140±4	139±5	0.174
eGFR (mL/min/1.73 m2)	52±23	51±23	0.784	48±20	47±21	0.811
HbA1c (%)	7.4±1.0	7.1±1.1	0.280	6.8±0.9	7.1±0.9	0.248
Medication
Insulin	4 (9)	2 (5)	0.450	3 (8)	3 (8)	0.919
Sulphonylurea	7 (16)	5 (13)	0.625	8 (22)	7 (18)	0.644
Biguanide	7 (16)	5 (13)	0.625	1 (3)	2 (5)	0.604
Pioglitazone	0 (0)	0 (0)	1.000	0 (0)	1(3)	0.333
α-Glucosidase inhibitor	8 (19)	6 (15)	0.661	7 (19)	4 (10)	0.261
Diuretics	38 (88)	34 (85)	0.651	27 (75)	31 (79)	0.643
β-blocker	35 (81)	32 (80)	0.872	27 (75)	28 (72)	0.754
ACEI/ARB	31 (72)	27 (68)	0.649	28 (78)	28 (72)	0.552
CCB	9 (21)	9 (23)	0.862	15 (42)	18 (46)	0.696
Aldosterone antagonist	29 (67)	26 (65)	0.814	22 (61)	23 (59)	0.850
Statin	18 (42)	19 (48)	0.606	21 (58)	16 (41)	0.134

Data given as mean±SD or as n (%). HF, heart failure. Other abbreviations as in Table 1.

Figure 3.

Kaplan-Meier survival curves for (A,C) all-cause mortality and (B,D) composite of cardiovascular death and hospitalization in (A,B) heart failure with reduced ejection fraction (HFrEF) and (C,D) heart failure with preserved ejection fraction (HFpEF), according to use of dipeptidyl peptidase-4 inhibitors (DPP-4i).

Change in Echocardiographic Parameters

In patients with 1-year follow-up echocardiography in the propensity-matched cohort, we assessed change in echocardiographic parameters (Table 4). We excluded 8 patients in the DPP-4i group and 13 patients in the non-DPP-4i group who died before follow-up echocardiography. Significant improvement in LVEF (DPP-4i, 44±15 to 50±14%; non-DPP-4i, 42±15 to 56±14%) and decrease of LV end-diastolic diameter (DPP-4i, 55.7±9.3 to 53.8±8.5 mm; non-DPP-4i, 55.1±10.2 to 50.8±8.3 mm) were observed in both groups during echocardiographic follow-up. In contrast, significant decrease in LV end-diastolic volume (DPP-4i, 117±56 to 106±53 mL; non-DPP-4i, 111±67 to 95±37 mL) and in LA volume index (DPP-4i, 44.3±31.1 to 40.3±43.5 mL/m²; non-DPP-4i, 50.5±22.3 to 34.5±28.8 mL) were observed only in the non-DPP-4i group. Change in LVEF and LA volume index in the non-DPP-4i group was significantly greater compared with the DPP-4i group. Change in intraventricular septum and posterior wall thickness, tricuspid regurgitation pressure gradient was not observed in either group.

Table 4. Serial Echocardiographic Characteristics

	DPP-4i (+) (n=71)			DPP-4i (−) (n=66)			P-value vs. change in DPP-4i (+)
	Baseline	Follow-up	Change	Baseline	Follow-up	Change
LV end-diastolic diameter (mm)	55.7±9.3	53.8±8.5*	−2.0 (−16.0 to 12.9)	55.1±10.2	50.8±8.3*	−4.3 (−15.2 to 6.0)	0.078
LV end-diastolic volume (mL)	117±56	106±53	−10.3 (−113 to 142)	111±67	95±37*	−15.6 (−80 to 52)	0.323
LV ejection fraction (%)	44±15	50±14*	5.6 (−9.4 to 34.0)	42±15	56±14*	13.1 (−24.6 to 44.6)	0.010
Intraventricular septum thickness (mm)	9.6±1.8	9.8±2.8	0.2 (−4.3 to 10.0)	10.0±2.2	9.8±1.7	−0.2 (−3.0 to 3.0)	0.473
Posterior wall thickness (mm)	9.6±1.5	9.5±1.5	−0.2 (−3.0 to 4.1)	9.6±1.7	9.8±1.5	0.2 (−3.0 to 3.0)	0.209
Relative wall thickness	0.35±0.09	0.37±0.10	0.01 (−0.14 to 0.25)	0.36±0.11	0.40±0.09*	0.04 (−0.1 to 0.20)	0.202
LAVI (mL/m2)	44.3±31.1	40.3±43.5	−4.1 (37.4 to 24.0)	50.5±22.3	34.5±28.8*	−16.0 (−71.6 to 68.8)	0.042
TRPG (mmHg)	29±13	38±11	8.6 (−23.0 to 29.6)	31±13	37±15	6.5 (−24.0 to 41.3)	0.888

Data given as mean±SD or median (IQR). *P<0.05 vs baseline. LAVI, left atrial volume index; LV, left ventricular; TRPG, tricuspid regurgitation pressure gradient. Other abbreviations as in Table 1.

Discussion

The present study is one of the first to evaluate the effects of DPP-4i on cardiovascular outcome and cardiac function in DM patients with HF. Given that some previous randomized clinical trials included few HF patients, the efficacy of DPP-4i for patients with HF has not been fully established. The major findings of the present study are that (1) DPP-4i does not appear to increase the risk of adverse cardiovascular outcomes in DM patients with HF; (2) DPP-4i may improve cardiovascular outcomes in DM patients with HFpEF; and (3) change in LVEF and LV reverse remodeling in the non-DPP-4i group were greater compared with the DPP-4i group.

Three large clinical trials showed that DPP-4i do not increase the risk of ischemic stroke or myocardial infarction.^8,9,11 Two trials, however, showed that saxagliptin (the SAVOR-TIMI 53 trial) and alogliptin (the EXAMINE trial) increase the risk of HF vs. placebo.^8,9 In contrast to clinical studies, animal experiments showed that DPP-4i have a cardioprotective effect; in particular, DPP-4i inhibits LV hypertrophy and fibrosis and decreases blood pressure. Therefore, DPP-4i might be more effective in HFpEF, in which the increase in LA pressure due to the elevation of LV and arterial stiffness is the main pathophysiological feature that distinguishes it from HFrEF. The difference between the present study and the previous large clinical trials is that we limited the subjects to DM patients with HF. Despite the smaller number of subjects, targeting patients with a high risk of clinical events enables the investigation of the influence of DPP-4i on prognosis in greater detail. In the present study, DPP-4i did not increase all-cause mortality, similar to previous studies. In contrast to previous studies, in the present study DPP-4i did not increase the risk of HF. This difference is probably due to the differences in subject group. Furthermore, the significant improvement in the prognosis of HFpEF, for which DPP-4i seem to be more effective, reduced the risk of HF in the whole cohort of patients treated with DPP-4i.

Weir et al evaluated the effects of the DPP-4i sitagliptin in patients with type 2 DM and HF using a US commercial insurance claims database.²² Their study is one of the largest studies evaluating patients with DM and HF. They concluded that sitagliptin use is associated with an approximately 2-fold increased risk of HF-related hospitalizations in patients with type 2 DM and pre-existing HF (adjusted OR, 1.84; 95% CI: 1.16–2.92). In contrast, they also showed that sitagliptin tended to reduce the risk of all-cause hospital admission or death compared with no sitagliptin, although the association was not significant (adjusted OR, 0.84; 95% CI: 0.69–1.03). Accordingly, it remains unresolved as to whether DPP-4i should be used in patients with DM and HF. It is difficult to compare the severity of HF between the present and previous patients, because LVEF, BNP, and NYHA classification were not analyzed in the previous study. Moreover, both the average age (72.2 vs. 54.6 years) and prevalence of diuretic use (79.2% vs. 19.1%) were much higher in the present study. Thus, the subjects differed substantially between the present and previous studies, and the prevalence of severe HF was higher in the present study. In the present study DPP-4i did not increase the risk of cardiovascular events including HF hospitalization in more severe HF patients, and also reduced cardiovascular events in patients with HFpEF. Although it was not DPP-4i, the Functional Impact of GLP-1 (glucagon-like peptide-1) for HF Treatment (FIGHT) study tested whether a GLP-1 agonist, liraglutide, improved clinical stability in patients with DM, established HF and reduced LVEF.²³ That study noted non-significant increases in death or rehospitalization for HF in the GLP-1 agonist group (HR, 1.54; 95% CI: 0.97–2.46; log-rank P=0.07) even in patients with lower LVEF compared with the present HFrEF patients (25% vs. 33%). These results for the incretin-related drug may support and strengthen the present results.

The present preliminary data on change of echocardiographic parameters showed that significant decrease of LV end-diastolic volume and LA volume index were observed only in the non-DPP-4i group. Whereas improvement of LVEF was observed in both groups, change in LVEF in the non-DPP-4i group was significantly greater compared with the DPP-4i group. Namely, LV reverse remodeling was observed regardless of use of DPP-4i, but was more remarkable in the non-DPP-4i group. There are few reports on the effects of DPP-4i on cardiac function in humans. It is noteworthy that a randomized clinical trial, Vildagliptin in Ventricular Dysfunction Diabetes (VIVIDD) trial, which evaluated the effect of vildagliptin on LV function in patients with both type 2 DM and HF, reported that vildagliptin increased LV end-diastolic volume compared with placebo (a difference of 17.06 mL vs. placebo). Although the question of whether DPP-4i will increase the risk of HF has not been answered, there are presently no known mechanisms by which DPP-4i could precipitate HF. Given that DPP-4i stimulate the secretion of insulin, a possible mechanism is the volume overload induced by the secretion of insulin, which promotes sodium reabsorption.^24,25 Subanalysis from the SAVOR-TIMI 53 Randomized Trial showed that saxagliptin treatment was associated with hospitalization for HF, particular in patients at a high overall risk of HF (history of HF, impaired renal function, or elevated baseline NT-proBNP).²⁶ No volume overload, however, was observed in that trial because saxagliptin did not raise NT-proBNP. That study also did not provide data on baseline cardiac function. One explanation for the difference between those and the present results was that the present study had matched LVEF data at baseline. Furthermore, SAVOR-TIMI 53 did not suggest there was direct myocardial necrosis or inflammation triggered by saxagliptin because there were no significant differences in high-sensitivity troponin T or high-sensitivity C-reactive protein with saxagliptin compared with placebo. Therefore, DPP-4i may have an unknown mechanism that exacerbates cardiac function other than inflammation or volume overload. The present echocardiography data suggest that DPP-4i is associated with some unknown mechanism that attenuates LV reverse remodeling, while DPP-4i is reported to have protective effects on cardiovascular function in animal experiments. The present results suggest that the effects of DPP-4i on cardiovascular events may differ with respect to the severity of HF and the classification of cardiac function. Therefore, future prospective studies on each classification of cardiac function and HF severity are required.

Sodium glucose co-transporter 2 (SGLT2) inhibitors are newer anti-hyperglycemic agents that act by decreasing the reabsorption of filtered glucose, thereby increasing urinary glucose excretion in patients with DM. We did not include patients using SGLT2 inhibitors, because the present study started before SGLT2 inhibitors were widely used in Japan. In the recent EMPA-REG OUTCOME clinical trials, patients with type 2 DM who received empagliflozin had a higher risk of cardiovascular events than those who received placebo, but lower rates of the primary composite cardiovascular outcome and all-cause mortality.²⁷ On the basis of these findings, opportunities to select SGLT2 inhibitors for the treatment of DM with HF will increase in the future. Given, however, that SGLT2 inhibitors are associated with clinical risk of urinary tract infection and excessive weight loss, they are not appropriate for elderly or low-weight patients. In addition, the effects of SGLT2 inhibitors are limited in the case of severe renal dysfunction. Therefore, there will be many HF patients who are not suitable for SGLT2 inhibitor treatment. Given that DPP-4i have fewer contraindications, they are expected to be mainly used in patients with DM and HF in the future. Hence, it is important to establish the effects of DPP-4i in patients with HF. The present results will help to select good candidates for DPP-4i among patients with DM and HF.

Study Limitations

The present study had some potential limitations. First, this was an observational study, and the types of DPP-4i were not unified. The differences in the impact of various DPP-4i on clinical outcome remain controversial. Therefore, the present results are generalizable to all DPP-4i. Second, although DPP-4i were not withdrawn from any patients in the DPP-4i group in a short period of time, there might be some cross-over between the DPP-4i and non-DPP-4i groups. Third, the this study lacked data on NT-proBNP. Because BNP is a substrate for DPP-4, NT-proBNP may be a suitable biological biomarker for assessment of cardiac function in patients treated with DPP-4i.

Finally, we used propensity score matching to adjust for parameters between the 2 groups, and sample size after propensity score matching was relatively small. Given that 25 variables were used for propensity score matching, matching between the 2 groups was considered optimal. Potential bias, however, cannot be entirely excluded. To resolve this issue, a randomized clinical study targeting a large number of patients with DM and HF is necessary.

Conclusions

In Japanese patients with type 2 DM and HF, DPP-4i did not increase the risk of adverse clinical outcomes and may improve the clinical outcome of HFpEF. The present results will help to select good candidates for DPP-4i use among patients with DM and HF.

Acknowledgments / Funding

None.

Conflict of Interest

None declared.

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