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 Table of Contents  
Year : 2017  |  Volume : 5  |  Issue : 2  |  Page : 61-67

Time to exacerbation of heart failure is longer in Malaysian population on dipeptidyl peptidase-4 inhibitor

1 Department of Internal Medicine, Faculty of Medicine, Universiti Teknologi MARA, Selangor, Malaysia
2 Department of Cardiology, Faculty of Medicine, Universiti Teknologi MARA, Selangor, Malaysia
3 Department of Population Health and Preventive Medicine (PHPM), Faculty of Medicine, Universiti Teknologi MARA, Selangor, Malaysia
4 Department of Internal Medicine, Faculty of Medicine; Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA, Selangor, Malaysia
5 Department of Cardiology, Faculty of Medicine; Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA, Selangor, Malaysia

Date of Web Publication20-Jun-2017

Correspondence Address:
S Kasim
Faculty of Medicine, UiTM, Kampus Sungai Buloh, Jalan Hospital, 47000 Sungai Buloh, Selangor
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/heartindia.heartindia_7_17

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Context: Diabetes mellitus is a recognized risk factor for heart failure. Dipeptidyl peptidase-4 inhibitors (DPP4i) are used in patients with diabetes largely due to its efficacy in glycated hemoglobin (HbA1c) reduction, neutral weight effect, and lower hypoglycemic events. New antidiabetic medications such as the glitazones have been linked with increasing mortality and heart failure exacerbations. The effect of DPP4i in heart failure has not been shown in a heterogenous Asian population.
Aims: The aim of this study was to assess incidence of heart failure and cardiovascular (CV) events in patients with diabetes with known coronary artery disease (CAD) treated with DPP4i.
Subjects and Methods: This was a single-center, retrospective analysis of patients with diabetes mellitus attending various specialist clinics in Universiti Teknologi MARA treated with available DPP4i agents from January 2013 to July 2015. Medical records were reviewed and data collected for demographic, anthropometric, laboratory, and treatment modalities. Endpoints include changes in body weight, body mass index, lipid, renal profile, and CV events during follow-up.
Results: Three hundred and twenty-three patients with diabetes were screened and 307 fulfilled the inclusion criteria. Fifty-four were on linagliptin, 115 were on vildagliptin, and 154 were on saxagliptin. Majority of patients (87.6%) had uncontrolled diabetes at baseline (HbA1c, %) (8.9 ± 2.07). There was a significant reduction in HbA1c from baseline to visit 1 at 3 months (P = 0.000). Similarly, significant improvement in HbA1c seen from baseline to visit 1 (P = 0.000). A higher CV event rate was found between 20 and 30 weeks of therapy with DPP4i. The cumulative survival was 99.5% at 20 weeks and reduced to 98.75% at 30 weeks (P = 0.033). There were seven reported events (0.98%) due to heart failure or acute coronary syndrome. These participants had higher baseline HbA1c and creatinine compared to the overall cohort.
Conclusions: Higher CV events were seen in diabetic patients with known CAD treated with DPP4i between 20 and 30 weeks of therapy and occurred earlier in patients with chronic kidney disease. This is later than published data and raises the need to monitor this group of patients for symptoms of heart failure beyond conventional monitoring.

Keywords: Diabetes mellitus, dipeptidyl peptidase-4 inhibitor, heart failure

How to cite this article:
Hasan J, Khir R N, Saman M A, Ibrahim K S, Ismail J R, Ghani R A, Lim C W, Ibrahim Z, Rahman E A, Chua N, Abidin H, Arshad M, Kasim S. Time to exacerbation of heart failure is longer in Malaysian population on dipeptidyl peptidase-4 inhibitor. Heart India 2017;5:61-7

How to cite this URL:
Hasan J, Khir R N, Saman M A, Ibrahim K S, Ismail J R, Ghani R A, Lim C W, Ibrahim Z, Rahman E A, Chua N, Abidin H, Arshad M, Kasim S. Time to exacerbation of heart failure is longer in Malaysian population on dipeptidyl peptidase-4 inhibitor. Heart India [serial online] 2017 [cited 2018 Jul 20];5:61-7. Available from: http://www.heartindia.net/text.asp?2017/5/2/61/208562

  Introduction Top

Diabetes mellitus is a recognized strong independent risk factor for cardiovascular (CV) disease and heightens the risk for heart failure. Many studies have shown that patients with diabetes have mortality and morbidity rates that were similar to any CV event.[1],[2],[3] In combination with heart failure, they have a higher mortality rate after hospitalization and portends a poorer prognosis.[4] Diabetes is associated with higher prevalence of renal dysfunction and worse maximal exercise capacity.[5] Factors that may promote this finding include activation of pro-inflammatory, prooxidative, and profibrotic pathways.[6] The Action to Control Cardiovascular Risk in Diabetes trial had shown that intensive glycemic control alone could not modify this risk thus raises the question of alternative mechanism in the pathophysiology of diabetic heart failure.[7] Dipeptidyl peptidase-4 inhibitor (DPP4i) is an incretin-based therapy that is used widely due to its efficacy, weight-neutral, lower risk of hypoglycemia, and fewer gastrointestinal side effects. The need to identify agents that can be used safely in patients with or at risk of developing heart failure remains an important clinical challenge in the light of recent controversy involving rosiglitazone.[8] We conducted a retrospective study to look at CV events particularly heart failure in patients treated with DPP4i.

  Subjects and Methods Top

This was a retrospective study involving type 2 diabetes patients treated with DPP4i in various clinics in Universiti Teknologi MARA (UiTM) from January 2013 to July 2015. Endpoints include CV events including hospitalization for heart failure, coronary revascularization, episodes of unstable angina, or death.

Inclusion and exclusion criteria

All the patients with diabetes who were prescribed DPP4i were included in the study. Patients were identified from UiTM specialist clinics (endocrine, cardiology, primary care, and internal medicine). We included those patients between the ages of 18 and 80 years. Exclusion criteria included patients who were lost to follow-up and those with missing data.

Study design

The study was conducted from July 2015 to October 2015. We reviewed pharmacy prescription database and data from the hospital medical records. Demographic, anthropometric, clinical, and laboratory data were collected. Data at each visit were recorded as V0 (baseline), V1 ( first subsequent visit), and V2(second subsequent visit). Sequential blood pressure (BP), weight, height, body mass index (BMI), and blood samples were obtained through standard procedures. Follow-up were ascertained through medical records. Missing follow-up data were followed up by a telephone interview to ascertain CV endpoints.

Statistical analysis

Data were analyzed using the SPSS statistical package version 22.0 (SPSS Inc., Chicago, IL, USA). Normally distributed data were expressed as mean ± standard deviation. The nonnormally distributed data were subjected to nonparametric testing and reported as median ± interquartile range. Student's t-test was used for comparison of quantitative data. Chi-square test was used to compare those normally distributed variables. Analysis of the CV events and death from any cause were performed with the use of time-to-event methods in weeks. Incident of outcome was compared with the use of Fisher's exact test. Event rates were expressed as the percentage of events per total follow-up. Kaplan–Meier estimates were used to obtain the proportion of patients who had a cumulative event during the follow-up and tested by log-rank Mantel-Cox. A P < 0.05 was taken as statistically significant.

  Results Top

A total of 323 patients were identified. Of this, 54 patients were prescribed linagliptin (Trajenta, Boehringer Ingelheim) from May 21, 2014 to June 23, 2015. One hundred and fifteen were prescribed vildagliptin (Galvusmet, Novartis) from July 18, 2013 to August 23, 2015. The remaining 154 patients were prescribed saxagliptin (Kombiglyze, AstraZeneca) from December 26, 2013 to June 23, 2015. Three hundred and seven had met the inclusion criteria, and total number according to prescription list for trajenta, galvusmet, kombiglyze was 53, 111, and 143, respectively. Those excluded were due to grossly missing data. The flowchart for analysis is shown in the following [Figure 1].
Figure 1: Flowchart of data analysis

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The baseline demographic and characteristics are shown in [Table 1]. The mean age was 56-year-old, concurrent with the national data on diabetes mellitus and ischemic heart disease (IHD). Majority of the patients (52.4%) has underlying established IHD or coronary artery disease (CAD) as well as hypertension (92.5%). The mean estimated glomerular filtration rate (eGFR) in these patients was 90 ml/min/1.73 m 2 by modification of diet in renal disease formula. Majority of them (80.5%) fell under chronic kidney disease (CKD) Stage II. Only 9 (2.9%) patients with advanced CKD Stage IV and V were prescribed DPP4i by the doctors.
Table 1: Baseline patients characteristic

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A majority of the study cohort had uncontrolled diabetes at baseline (87.6%). Their mean glycated hemoglobin (HbA1c) was 8.9% ± 2.07% before starting DPP4i. Subsequently, there was a significant improvement in HbA1c at visit 1 at 8.2% ± 1.56% (P = 0.000). However, there was no significant decline at visit 2 with HbA1c of 7.9% ± 1.77% (P = 0.174). The change in HbA1c at visit 1 was 0.89 ± 1.62 and the HbA1c change at visit 2 was 0.16 ± 1.39. It showed a significant HbA1c improvement from visit 1 to visit 2 (P = 0.000*). The mean BMI of our patients was 28.8 (±6.9). The weight change at visit 1 was −0.10 ± 2.51. While the weight change at visit 2 was −1.12 ± 9.38. There was no significant change in body weight throughout the subsequent visit 1 and visit 2 (P = 0.203).

Out of these 307 patients, only 164 had a baseline echocardiogram at initiation of DPP4i. One hundred and thirteen patients were found to have preserved ejection fraction (EF) defined as more than 45% while 51 patients had impaired or poor EF. They were found to have some evidence of diastolic dysfunctions regardless of the EF, defined by abnormal early diastolic filling over atrial contraction (E/A) ratio with a mean of 0.6 (±1.0).

All patients demonstrated significant reductions in total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein (HDL-C), and triglycerides (TGs) levels after at least 3 months of treatment and a further improvement after 6 months. The HDL-C improvement after visit 1 and visit 2 was statistically significant (P = 0.039*). However, there were no significant changes seen in TG and LDL-C levels. The sequential HbA1c, weight, and lipid profile changes are summarized in [Table 2].
Table 2: Change in weight, body mass index, and blood parameters

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Kaplan–Meier analysis

We found no difference in the mean time-to-event between male and female (59.4 ± 0.25 and 58.9–59.9, respectively) as well as the presence of hypertension (log-rank Mantel-Cox λ2 0.353, P= 0.552). However, there were higher cumulative events in patients with established IHD/CAD who received DPP4i compared to those who did not receive the same medication, observed between 20 and 30 weeks. The cumulative survival was 99.5% at 20 weeks and reduced to 98.75% at 30 weeks of DPP4i (P = 0.033*). The survival functions in patients with underlying IHD/CAD against time-to-event are shown in [Figure 2].
Figure 2: Kaplan–Meier curve for the cumulative survival in patients with underlying ischemic heart disease/chronic kidney disease

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Hospitalization and events

Further analysis showed that in patients prescribed linagliptin, there were three reported events due to heart failure or acute coronary syndrome [Table 3]. This amounts to 0.98% of total number of patients. While in patients who were prescribed vildagliptin and saxagliptin, 2 (0.65%) had been hospitalized for the same reasons. The time-to-event in weeks for these patients was between 20.6 and 34 weeks from the start of DPP4i. One death reported to have occurred in the saxagliptin group, but these data were from extended follow-up occurred at 62 weeks and not related to any CV event. Analysis of these seven affected patients showed mean age of 57.1 ± 13. Their BMI was 27.2 ± 2.9 and mean weight was 70.3 ± 12.7. The mean HbA1c was 9.8 ± 2.3. Serum creatinine was 110.6 ± 67 mmol/L with eGFR of 73 ± 30. Their LDL-C was 2.64 ± 1.65, HDL-C 0.99 ± 0.49, and TG 1.44 ± 1.06. The baseline demographic and characteristics of these seven patients are listed in [Table 4].
Table 3: Hospitalization for heart failure or acute coronary syndrome and death from any cause

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Table 4: Characteristics of patients with events

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  Discussion Top

Findings from SAVOR-TIMI 53 has demonstrated slightly higher risk for heart failure within the first 6 months of saxagliptin despite having no significant difference in the overall primary and secondary endpoints.[9] This had imposed concerns among clinicians as there was also a trend toward an increase in hospitalization for heart failure in EXAMINE trial involving alogliptin.[10] Another data from a study with vildagliptin [11] have shown an increase in both systolic and diastolic pressure, which could be an additional risk factor for heart failure. However, the exact mechanism of heart failure in those patients remained vague. There was no echocardiography data from these previous trials to ascertain the type and degree of heart failure that has occurred in the patients affected. In the most recent study,[12] there was no significant difference in the primary and overall outcome in patients treated with sitagliptin.

The remodeling theory through cardiac fibrosis

DPP4i are drugs that act by preserving incretin hormones and promoting postprandial insulin secretions.[13] It is known to be present in many cells and tissues. Its effects extend beyond purely metabolic aspects. In experimental models, DPP4i has demonstrated some cardioprotective effects. A preclinical study with sitagliptin showed the presence of cardioprotective proteins with DPP4i in murine heart.[14] Another study showed a reduction of BP in rat models.[15] Makdissi et al. showed potential benefits of cellular pleiotropic effects of DPP-4i to CV endothelial system.[16] However, there is growing evidence in recent years questioning the cardioprotection of DPP4 inhibition in real-life clinical settings.

DPP4i is safe from CV standpoints at least in the short-term, but there has been insufficient long-term data. From our analysis, event had occurred in seven patients. The finding began to emerge after 20–30 weeks of DPP4i. Our findings concurred with Scirica et al. who demonstrated a 27% increased relative risk after 24 weeks of therapy, most prominently after 12 weeks. The investigators found some signals to identify group of patients who were at higher risk to develop heart failure. These include prior history of heart failure, high atrial natriuretic peptides level, and underlying CKD.[9] Our seven patients with events had a higher baseline serum creatinine level compared to the total population (110.57 ± 67.17 vs. 86.2 ± 50.8 μmol/L). Some previous studies suggested a strong cardiorenal pathophysiology with a higher mortality in CKD patient.[17] Furthermore, it has been shown that there were reduced capillary density, increased vascular stiffness, and reduced smooth muscle density in CKD-associated myocardial changes.[18] Smaller study has even suggested worsening of endothelial function as depicted by reduced flow-mediated dilatation of the brachial artery with DPP4i.[19] Impairment of these endothelial functions could reflect the early strain on myocardium and loss of myocardial elasticity. Patients with CKD are known to have chronic neurohormonal alterations of the vessels leading to hypertension.[20],[21]

Increased left ventricular wall strain from pressure overload as a consequence of hypertension and vascular stiffness may alter the composition of the myocardium.[22] Hence, vascular stiffness as a result of endothelial dysfunction accentuated by CKD-associated abnormalities as described above may be one of the key etiological aspects to why they developed early heart failure.

Another intriguing hypothesis would be the probability of DPP4i causing impairment of ventricular function through promoting early cardiac fibrosis. Our study found that except for one patient, 6 had baseline diastolic dysfunctions. Mulvihill et al. recently showed that using DPP4i, cardiac fibrosis had occurred significantly earlier.[23] In their preclinical study, the ratio of the rise in pressure during isovolumetric contraction over isovolumetric contraction time (dp/dt) was increased and the ratio of peak early to late diastolic filling velocity (E/A) worsened in these diabetic models. The etiopathophysiology could be continuous oxidative stressors which dysregulate expression of the genes or proteins that control inflammation.[24],[25],[26] Other experimental in vitro studies showed that diabetic rats exhibited left ventricular diastolic dysfunction with enhanced interstitial fibrosis due to increased ratio of circulating matrix metalloproteinase-2 (MMP-2).[27],[28] MMP-2 is central in collagen metabolism and cardiac remodeling. It is being synthesized in a DPP4–dependent manner.[29] The exaggerated collagen synthesis with depressed collagen degradation might explain temporal relation of myocardial fibrosis with DPP4 inhibition.

Based on our study, majority of patients had uncontrolled diabetes and may explain accelerated events, especially those with underlying IHD. The baseline HbA1c of those who had CV events was 9.8% compared to those who did not have CV events with HbA1c 8.9%. Confounding this, there was also a postulated theory that hyperglycemia promotes cardiac metabolic dysregulation through glycolytic and free fatty acid oxidation pathway. Glucotoxicity induces inflammation, oxidation, and fibrosis, which have been described earlier in experimental model.[30] Therefore, we hypothesize the possible link between higher HbA1c in developing heart failure at much early stage. Landmark clinical trials have shown that early intensification of glycemic control could confer benefits in delaying the onset or progression of macrovascular complications including myocardial infarctions and heart failure events, especially with concomitant use of sulfonylurea.[31],[32] Perhaps, noncompliance is a major factor in determining control of diabetes in our local population. To address this, physicians and patients really need to enhance compliance through all available pharmacological as well as nonpharmacological strategies.

Putting the way forward

There are limitations to this particular study that have to be acknowledged. First, with regard to its retrospective nature, it was not designed to generate conclusion. We noted that longer observational studies are thus needed to validate the earlier observations. Further clinical studies on possible mechanisms of DPP4i on the myocardium, especially looking at the effects of early and delayed endothelial dysfunction, inflammatory mediators, cellular oxidative stressors, and cardiac fibrosis, would deepen our understanding of the potential benefit or harm of DPP4i on the heart.(note: TECOS, SAVOUR TIMI 53 are already long-term studies looking at CV events.) Second, earlier event occurred in patients with underlying CKD can be explained through few mechanisms. Vigilance in this at higher risk group should be carried out at all time.

Very few studies have been conducted in real-life practice within our local setting where the risk factors may be heterogenous. The study population was of a sizable number of unselected, real-life patients, with a favorable follow-up rate and attainment of reduction in HbA1c by 0.5%–0.9% during each visit. Even though the plausible causes of the events could not be confirmed, we could recommend that vigilance should be implemented within clinics that routinely treat similar high risk. Bigger on-going multicenter clinical trial such as CAROLINA,[33] which is expected to finish by 2018, might be able to provide more solid evidence.

  Conclusions Top

Our data suggested that there was temporal signal of heart failure with the use of DPP4i, which occurred between 20 and 30 weeks in patients with diabetes with underlying IHD. It also occurred slightly higher in patients with impaired renal function or underlying CKD. This warrants caution on initiation of DPP4i, especially in those with high-risk factors. Clinicians should stratify patients according to their risk profiles and provide appropriate individualized treatments based on the current evidence.


We would like to thank our colleagues and staffs of our center, particularly the record office personnel for assistance in tracing all the medical records of our patients. We would also like to thank the Department of Population and Preventive Health Medicine, for assistance with statistical analyses. Finally, we would like to thank the Faculty of Medicine, UiTM Sg Buloh, for allowing us to produce these data.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3], [Table 4]


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