Type 2 diabetes is a chronic and progressive disease that is an increasing global health problem. It has considerable impact on morbidity and mortality, particularly on cardiovascular complications.1) To delay or prevent these complications, the management of type 2 diabetes through lifestyle modifications and the selection of appropriate glucose-lowering drugs are necessary.2)

Dipeptidyl peptidase-4 inhibitors (DPP-4is) are a relatively new class of oral hypoglycemic agents for treating type 2 diabetes; their effects are mediated through the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Previous studies have suggested that DPP-4i as a monotherapy or in combination with other oral hypoglycemic agents has potentially beneficial effects on cardiovascular outcomes.3)4)5)6) A recent study by Ha et al.,6) based on the 2011–2015 Korean National Health Insurance Service (NHIS) database, reported that people with type 2 diabetes who added a DPP-4i as a second-line drug to metformin had lower risks of cardiovascular disease (CVD) and all-cause mortality, compared to those who added sulfonylurea. However, there are some practical differences between the DPP-4is such as duration of action, metabolism, elimination, and isolated compound-specific characteristics.7) Although there have been randomized controlled trials studying the effects of each DPP-4i on CVD, the results have been inconsistent,8)9)10) and there is little evidence comparing the effects of DPP-4i on CVD using large-scale observational studies.11)12)13)

We conducted a real-world cohort study to compare the CVD risks of different DPP-4is among people with type 2 diabetes through an analysis of a nationwide health insurance database in Korea.

The current analyses were based on a dataset from the NHIS, the compulsory single-payer national health care coverage system in South Korea. The NHIS claims database includes a de-identified research dataset of demographic information, disease diagnoses, therapeutic procedures, and drug prescriptions. In addition, the NHIS requires biennial health screening tests that include health questionnaire surveys, physical examinations, and biochemical test results.

Among people with type 2 diabetes (International Classification of Diseases, 10th Edition [ICD-10] codes E11–E14), we selected a subset who were newly prescribed DPP-4is for at least 90 days between January 2013 and June 2015. DPP-4is were limited to the 5 most common drugs: sitagliptin, vildagliptin, saxagliptin, linagliptin, and gemigliptin. The start date of medication administration was defined as the index date. We excluded people aged <30 years or >90 years at the index date, and/or who had a history of CVD or cancer between the year prior to the index date and within 90 days after the index (Figure 1). The outcome was the modified major adverse cardiovascular events, defined as hospitalized myocardial infarction (ICD-10 codes I21–I23), hospitalized stroke (ICD-10 codes I60–I69), or all-cause death. The date of CVD onset was the date of the first occurrence of the event. This study was performed as an “intention to treat” analysis. The end of follow-up was the CVD diagnosis or the end of the study period (June 30, 2015), or whichever occurred first.

We used Kaplan-Meier analyses to compare cumulative incidence of CVD by the 5 different DPP-4is. A Cox proportional hazards model was used to estimate the relationships between the 5 different DPP-4is and CVD risk, calculating hazard ratios (HRs) and 95% confidence intervals (CIs) and adjusting for potential confounders. Although the NHIS claims database included major risk factor variables, there may be some unmeasured confounding factors. Therefore, we utilized 2 approaches. First, we conducted the main analysis, including the following factors as confounders: sex, age, duration of DPP-4i use, use of other glucose-lowering drugs (metformin, sulfonylurea, thiazolidinedione, or insulin), use of antiplatelet agents (Anatomical Therapeutic Chemical [ATC] code B01), calendar year, Charlson comorbidity index (CCI), and comorbidities.14) The comorbid conditions included hypertension (ICD-10 codes I10–I15 and/or ATC codes C02–C03, or C07–C09), dyslipidemia (ICD-10 code E78 and/or ATC code C10), atrial fibrillation (ICD-10 code I48), chronic kidney disease (ICD-10 code N18), and microvascular complications of diabetes including retinopathy (ICD-10 codes E11.3, E12.3, E13.3, E14.3, or H36.0), neuropathy (ICD-10 codes E11.4, E12.4, E13.4, E14.4, or G63.2), or nephropathy (ICD-10 codes E11.2, E12.2, E13.2, E14.2, or N08.3) within the year prior to the index date. Second, we conducted additional analysis only on those who had health screening data collected within the 2 years prior to the index date. These analyses included sex, age, duration of DPP-4i use, use of other glucose-lowering drugs (metformin, sulfonylurea, thiazolidinedione, or insulin), calendar year, body mass index (BMI), waist circumference, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, fasting glucose, serum creatinine, smoking status (yes or no), family history of stroke and heart disease, and CCI. All of the analyses were conducted using SAS software, version 9.4 (SAS Institute Inc., Cary, NC, USA).

A total of 534,327 people with type 2 diabetes who were newly prescribed DPP-4is (167,157 sitagliptin users, 67,412 vildagliptin users, 29,479 saxagliptin users, 220,672 linagliptin users, and 49,607 gemigliptin users) were identified. The age and sex distribution of the users of each DPP-4i were similar, with a mean age of approximately 60 years; approximately 57.1% of the people were male (Table 1). The baseline characteristics of the analysis of the health screening data was summarized in Supplementary Table 1.

Table 2 and Figure 2 shows the CVD risk for users of each DPP-4i compared to those treated with sitagliptin. In the main analysis, CVD risk was significantly lower in saxagliptin users (HR, 0.76; 95% CI, 0.71–0.81; p<0.001), linagliptin users (HR, 0.95; 95% CI, 0.92–0.98; p<0.001) and gemigliptin users (HR, 0.84; 95% CI, 0.80–0.88; p<0.001) than in sitagliptin users after adjusting for all of the confounding variables. However, vildagliptin users were not significantly different from sitagliptin users in terms of CVD risk (HR, 0.97; 95% CI, 0.94–1.01; p=0.163). In addition, this statistical significance was retained saxagliptin, linagliptin, and gemigliptin users in the propensity score-matching analysis (data not shown). There was a difference in the significant associations of each events (death, myocardial infarction, and stroke) for each DPP-4i use (Supplementary Table 2). Because our analysis defined wash-out period as 90 days, we did a further analysis with 180, 270, and 360 days wash-out period. And, different wash-out period did not severely influence the association (Supplementary Table 3). When we divided subgroup by duration of DPP-4i, saxagliptin and gemigliptin users had lower risk of CVD in all groups (Supplementary Table 4).

In the analysis of health screening data, saxagliptin and gemigliptin users had significantly lower CVD risk than sitagliptin users after adjusting for sex, age, duration of DPP-4i use, use of other glucose-lowering drugs, calendar year, CCI, BMI, waist circumference, systolic blood pressure, blood lipid profile, fasting glucose, serum creatinine, cigarette smoking, and family histories of stroke and heart disease, which were measured ≤2 years before DPP-4i therapy initiation (saxagliptin users, HR, 0.71; 95% CI, 0.58–0.86; p<0.001; gemigliptin users, HR, 0.80; 95% CI, 0.69–0.91; p=0.001) (Table 2 and Figure 2).

We repeated the main analysis for subgroups categorized by sex, age, hypertension, dyslipidemia, and microvascular complication. Sex, age, microvascular complication did not modify the associations. However, when classified as hypertension, saxagliptin, linagliptin, and gemigliptin users had significantly lower risk of CVD compare to sitagliptin users in people with hypertension. However, this statistical significance was retained only saxagliptin users in people without hypertension. When classified as dyslipidemia, saxagliptin, linagliptin, and gemigliptin users had significantly lower risk of CVD compare to sitagliptin users in people with dyslipidemia. However, this statistical significance was not found in people without dyslipidemia (Figure 3). When classified as use of statin, saxagliptin, linagliptin, and gemigliptin users had significantly lower risk of CVD compare to sitagliptin users regardless of use of statin (data not shown).

In this analysis of nationwide real-world data, we observed that the use of saxagliptin, linagliptin, or gemigliptin was significantly associated with decreased CVD risk compared to sitagliptin use.

Previous studies have reported associations between specific DPP-4i agents and CVD risk. A large observational study in the United States demonstrated that new users of sitagliptin or saxagliptin had no associated risk for heart failure compared to pioglitazone users.13) Based on a large national study using commercially insured claims and an integrated laboratory database in the United States, sitagliptin use did not increase the risks of all-cause hospital admission or death compared to other glucose-lowering agents.15) In a clinical trial, using vildagliptin as an add-on medication to metformin resulted in a larger decrease in glycosylated hemoglobin than using pioglitazone as an add-on medication (−0.94% vs. −0.6%; p=0.010).16) However, real-world data from 5 European electronic healthcare databases showed that vildagliptin had no association with CVD compared to other glucose-lowering agents (range of adjusted incidence rate ratios=0.22–1.02).17) Using the Korean Health Insurance Review and Assessment Service database, new users of sitagliptin and vildagliptin had no associations with CVD compared to pioglitazone users.12) In a clinical trial, linagliptin was associated with significantly lower risk of CVD than sulfonylurea glimepiride (relative risk=0.46; p=0.021).18) Gemigliptin demonstrated a protective effect against CVD.19) Pooled meta-analyses with DPP-4i (sitagliptin, vildagliptin, saxagliptin, and linagliptin) reported significant decreases in cardiovascular events.20)21)22)23)24)

The risk of CVD, particularly heart failure, for DPP-4i users has been controversial in randomized controlled trials. The SAVOR-TIMI 53 trial reported that saxagliptin showed no significant associations with cardiovascular risks including cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, hospitalization for unstable angina, coronary revascularization, or heart failure compared to a placebo group (HR, 1.02; p=0.660). When classified as subtypes of CVD, saxagliptin had a significantly increased risk for only heart failure (HR, 1.27; p=0.007), but not for other subtypes of CVD.10) The TECOS trial showed that sitagliptin had no significant associations with CVD, comprising cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina (HR, 0.98; p=0.650); but also heart failure (HR, 1.00; p=0.980).8) However, there were no significant differences in CVD risk between saxagliptin users and sitagliptin users based on a United States insurance claims database.11)

DPP-4is are glucose-lowering agents that inhibit the metabolism of the incretin hormones GLP-1 and GIP.25) Experimental and preliminary clinical data have reported that GLP-1 has beneficial cardiovascular effects.26)27) Although different DPP-4is act on the human body in similar ways, there are some intrinsic pharmacological differences.7) In particular, the differential selectivities among DPP-4is for non-GLP-1 substrates may cause a risk of hospitalizations for heart failure.28) However, the reasons for the different effects on CVD among the classes of DPP-4i are unclear.

To the best of our knowledge, this study was the first to investigate the associations between DPP-4i and cardiovascular risk among people with type 2 diabetes using nationwide real-world data from Korea. Despite yielding several important findings, this study faced several limitations that should be considered when reviewing the results. First, there were potential misclassifications of outcomes because we used definitions based on diagnoses from health insurance claims data. However, previous validation studies for the identification of CVD events showed 71.4% for myocardial infarction and 83.4% for ischemic stroke.29)30) Second, as the mean follow-up period was relatively short, additional studies are needed to compare the long-term effects of the different DPP-4i. Finally, we cannot exclude the possibility of residual confounding by unmeasured or uncontrolled confounders such as duration of diabetes, time-varying confounders because this is an observational study using a health insurance claims database. Although the analysis of health screening data adjusting for clinical variables attenuate this concern, we still cannot completely rule out the possibility of residual confounding.

In conclusion, this analysis of nationwide real-world data from Korea suggests that compared to sitagliptin use, saxagliptin, linagliptin, and gemigliptin use was associated with a lower risk of cardiovascular events. Further large-scale observational studies evaluating the differences among DPP-4is in terms of cardiovascular benefits or risks are needed.