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. 2017 Sep 8;96(36):e7638. doi: 10.1097/MD.0000000000007638

Combination therapy of metformin plus dipeptidyl peptidase-4 inhibitor versus metformin plus sulfonylurea and their association with a decreased risk of cardiovascular disease in type 2 diabetes mellitus patients

Fei Wang a, Yuan He b, Rong Zhang a, Qiang Zeng a,∗, Xiaolan Zhao c,∗
Editor: Jongwha Chang
PMCID: PMC6393015  PMID: 28885325

Abstract

Background:

Clinical trials assessing the combination therapy of metformin plus dipeptidyl peptidase-4 inhibitors versus metformin plus Sulfonylureas on risk of cardiovascular disease, cardiovascular mortality and/or all-cause mortality in type 2 diabetes have shown conflicting results. We therefore evaluated the combination therapy on the risk of cardiovascular disease, cardiovascular mortality and/or all-cause mortality in type 2 diabetes.

Methods:

A systematic search of Medline/PubMed (from 2000 to September 2015), EMBASE (from 2000 to September 2015), and Web of Knowledge (from 2000 to September 2015) for research articles published in English was carried out to examine how combination therapy affects the risk of CVD mortality and/or all-cause mortality in T2DM patients. In addition, the risks of cardiovascular events, CVD mortality, and/or all-cause mortality as well as the adjusted relative risk (RR) or equivalent (hazard ratio or odds ratio) and the corresponding variance or equivalent are reported.

Results:

The accumulative RRs (95% confidence intervals) for T2DM patients treated with the combination therapy of metformin plus DPP-4 inhibitor versus metformin plus sulfonylurea were 0.71 (0.56–0.90) for nonfatal cardiovascular events, 1.001 (0.85–1.18) for fatal cardiovascular events, 0.58 (0.41–0.82) for CVD mortality, and 0.72 (0.59–0.87) for all-cause mortality.

Conclusions:

The combination therapy of metformin plus DPP-4 inhibitor significantly decreased the RR of nonfatal cardiovascular events, CVD mortality, and all-cause mortality, compared with the combination therapy of metformin plus sulfonylurea. However, the number fatal cardiovascular events (e.g., heart failure) was not significantly different between the 2 groups.

Keywords: adjusted relative risk, hazard ratio, type 2 diabetes mellitus

1. Introduction

As a global public health issue, type 2 diabetes mellitus (T2DM) affected approximately 347 million individuals worldwide in 2008, among whom 10% are adults.[1] With some association with microvascular and macrovascular morbidity and mortality, hyperglycemia has been targeted in the management of T2DM.[2] Moreover, patients with T2DM have a 2- to 4-fold higher risk of cardiovascular disease (CVD) and CVD mortality compared with patients without T2DM.[3] However, it has not been demonstrated by clinical trials that those with T2DM who have achieved normal glucose levels can lower their risk for cardiovascular events.

In 2012, the American Diabetes Association and the European Association for the Study of Diabetes proposed that metformin monotherapy was the first-line glucose-lowering drug treatment, without contraindications.[4] Unfortunately, many patients on metformin monotherapy failed to meet or keep glycemic control for a long period. Based on the 2009 guidelines of the National Institute for Health and Care Excellence (NICE), it is necessary to add a sulfonylurea to metformin therapy as long as this is not contraindicated by factors such as obesity or risk of hypoglycemia; otherwise, a dipeptidyl peptidase-4 (DPP-4) inhibitor or thiazolidinedione can be added. After the release of these guidelines, however, a greater understanding of alternative agents has been observed. Nonetheless, the choice of an additional therapeutic agent remains complex because the agents have to be compared with regard to their efficacy and safety.

Sulfonylureas have been the most widely used add-on to metformin therapy for several years, but they may increase cardiovascular risks.[5,6] In recent years, as a class of agents, DPP-4 inhibitors have been permitted to treat T2DM and to improve the control of glycemia by increasing incretin levels. In several clinical studies, metformin plus DPP-4 inhibitor achieved similar glucose control with a lower risk for CVD, CVD mortality, and all-cause mortality than metformin plus sulfonylurea.[7–9] However, Scirica et al have reported that adding a DPP-4 inhibitor to standard metformin therapy in T2DM patients ran a high risk for cardiovascular events.[10]

Given these inconsistencies in the literature, we performed a meta-analysis on the relationships of metformin plus DPP-4 inhibitor versus metformin plus sulfonylurea on CVD, CVD morbidity, and all-cause mortality in T2DM patients.

2. Methods

2.1. Literature search

A systematic search of Medline/PubMed (from 2000 to September 2015), EMBASE (from 2000 to September 2015), and Web of Knowledge (from 2000 to September 2015) for research articles published in English was carried out to examine how combination therapy affects the risk of CVD mortality and/or all-cause mortality in T2DM patients. The search was designed using the following key words or phrases: “dipeptidyl peptidase-4 inhibitors,” “DPP-4 inhibitors,” the names of individual available DPP-4 inhibitors (“alogliptin,” “dutogliptin,” “linagliptin,” “saxagliptin,” “sitagliptin,” and “vildagliptin”), “sulfonylurea,” sulfonylurea compounds (“glimepiride,” “acetohexamide,” “tolbutamide,” “tolazamide,” “glyburide,” “glipizide,” “biguanides,” and “chlorpropamide”), and the combination of “metformin” and “cardiovascular,” “stroke,” “myocardial infarction,” or “heart failure.” In the search, only studies of human subjects were selected. Two researchers assessed the relevance of the cited article abstracts. When at least one of the reviewers judged the abstracts to be pertinent, the studies were retrieved for further consideration. If there was a discrepancy, it was resolved by consensus. Sometimes, a third investigator was needed to be involved to reach a consensus. In the case of multiple reports from the same trial, the reviewers chose the most complete and/or more recently reported data.

2.2. Study selection

The inclusion criteria used were as follows: randomized clinical trials, case reports, or cohort studies that investigated the relationship of therapy with metformin plus DPP-4 inhibitor versus metformin plus sulfonylurea on the risk of CVD and/or mortality; the relative risk (RR) or equivalent (e.g., hazard ratio, odds ratio) and the corresponding variance or equivalent reported; and diagnosis of T2DM applying the standard criteria.

2.3. Data extraction

Two observers abstracted the data independently, and a senior investigator was required in the case of potential discrepancies. It was necessary to take the following events into account: cardiovascular events (e.g., nonfatal myocardial infarction, stroke); fatal heart failure; and death from any cause.

2.4. Study quality

To assess the quality of each study, the following criteria were followed: in the assessment of randomized controlled trials, both the quality of reporting of meta-analyses guidelines and the Jadad scale were used; cohort and case-control studies were assessed using the Newcastle–Ottawa scale; and it was necessary for the studies selected to have well-defined inclusion criteria for patients and clear definitions of treatment responses. To evaluate potential publication bias, Begg rank correlation test and Egger linear regression test were used.

2.5. Statistical analysis

All the analyses were based on previous published studies, thus no ethical approval and patient consent are required. To account for the possibility of events occurring in the treatment group versus the control group, the metan routine (STATA Stata Corp, version 12.0) was applied to calculate the RRs of the effect of randomized treatments.[11] It was necessary to make a separate calculation of the RR and 95% confidence interval (CI) for each outcome for each trial, with data grouped based on the intention-to-treat principle.[12] Pooled RRs underwent logarithmic transformation and were weighted for the inverse of variance. When heterogeneity failed to be explained, it was necessary to make an overall estimation of effect based on a fixed-effects model or a random-effects model. The Q statistic was applied to test the assumption of homogeneity between the treatment effects in different trials, and the I2 statistic was applied for further quantification. Significance was set as P < .1 or I2 ≥ 50%.

3. Results

3.1. Search results and characteristics of the study

Through electronic searches, 203 citations were identified based on the inclusion criteria, and 195 were excluded. A total of 139 studies were duplicates, 20 studies were reviews, 6 studies did not include a combination with metformin, 9 studies involved multiple drug combinations, and 21 studies did not report CVD or mortality to be an outcome (Fig. 1).

Figure 1.

Figure 1

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Flow chart summarizing the selection process.

Table 1  presents the characteristics of the studies.[7–9,12–16] Of the 8 included studies, 6 were retrospective cohort studies and 2 were randomized clinical trials. Of the 8 studies, 1 of them was executed in the United States, 1 in Denmark, 1 in the United Kingdom, 1 in Korea, 1 in Taiwan, 2 in Germany, and 1 in Canada. The number of participants ranged from 616 in the study by Gitt et al[13] to 328,283 in the study by Seong et al.[7] The average patient age ranged between 57.0 and 67.7 years. The average time of follow-up was 1.0 to 4.0 years. Among the studies, 8 stated nonfatal cardiovascular events, 5 reported fatal cardiovascular events, 2 reported cardiovascular mortalities, and 5 reported all-cause mortality. Of the 451,418 participants included in these studies, 342,595 participants received metformin plus sulfonylurea combination therapy, and 108,823 participants received metformin plus DPP-4 inhibitor combination therapy.

Table 1.

Characteristics of observational studies of metformin plus dipeptidyl peptidase-4 inhibitor versus metformin plus sulfonylurea and their association with a decreased risk of cardiovascular disease, cardiovascular mortality, and/or all-cause mortality.

3.1.

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Table 1 (Continued).

Characteristics of observational studies of metformin plus dipeptidyl peptidase-4 inhibitor versus metformin plus sulfonylurea and their association with a decreased risk of cardiovascular disease, cardiovascular mortality, and/or all-cause mortality.

3.1.

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3.2. Study quality

According to the quality assessment of the respective studies, randomized controlled trials had Jadad scores that ranged between 1 and 5. Of the randomized controlled trials that were withdrawn from this study, 2 full studies[12,13] failed to describe the method of randomization in detail, and 3 studies received Jadad scores of 2. All trials had pointed out inclusion criteria for patients as well as definitions of the diagnosis and treatment responses. Moreover, there were comparable baseline characteristics of all study populations between the metformin plus DPP-4 inhibitor and metformin plus sulfonylurea groups. There was no evidence of publication bias by rank correlation or regression testing (Fig. 2).

Figure 2.

Figure 2

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Funnel pool: comparison of metformin plus dipeptidyl peptidase-4 inhibitor versus metformin plus sulfonylurea treatment outcome of a risk of no fatal CVD (A) and all-cause mortality (B) in Type 2 diabetes mellitus patients. CVD = cardiovascular disease.

3.3. Cardiovascular events

Figure 3 depicts the nonfatal cardiovascular events and fatal cardiovascular events based on the random-effects models, pooling the adjusted RRs for association with combination therapy of metformin and DPP-4 inhibitor versus metformin and sulfonylurea. By sensitivity analysis, the pooled RR estimates (95% CI) for the nonfatal cardiovascular events and fatal cardiovascular events were 0.71 (0.56–0.90), I2 = 88.1%, P = .004 and 1.001 (0.85–1.18), I2 = 24.9%, P = .99, respectively. Statistically, the pooled RR estimates were not significant for fatal cardiovascular events, while the use of combination therapy of metformin plus DPP-4 inhibitor was significantly related to a decreased risk of nonfatal cardiovascular events.

Figure 3.

Figure 3

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Forest plot: relative risk (RR) estimates and 95% confidence intervals (CIs) for the nonfatal cardiovascular events (A) and fatal cardiovascular events (B) associated with the combination therapy of metformin plus DPP-4 inhibitor versus metformin plus sulfonylurea by study and pooled along with the proportion of events for each outcome. DPP-4 = dipeptidyl peptidase-4 inhibitors.

By excluding the study by Ou et al,[14] a further sensitivity analysis was carried out in which the outcome was inferior. The heterogeneity of nonfatal cardiovascular events and fatal cardiovascular events all became small (I2 = 0%). The combination therapy of metformin plus DPP-4 inhibitor had a significantly lower risk of nonfatal cardiovascular events, with a pooled estimate of 0.68 (0.62–0.75), P < .01, compared with metformin plus sulfonylurea combination therapy (Fig. 4). However, fatal cardiovascular events were not statistically significant, with a pooled estimate of 0.84 (0.66–1.06), P = .15. The outcome seemed to be relatively stable.

Figure 4.

Figure 4

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Forest plot: relative risk (RR) estimates and 95% confidence intervals (CIs) for the nonfatal cardiovascular events (A) and fatal cardiovascular events (B) associated with the combination therapy of metformin plus DPP-4 inhibitor versus metformin plus sulfonylurea, excluding the study by Ou et al and pooled along with proportion of events for each outcome. DPP-4 = dipeptidyl peptidase-4 inhibitors.

3.4. Cardiovascular mortality and all-cause mortality

Figure 5 clearly shows the study-specific and pooled RRs of CVD mortality and all-cause mortality for association with metformin plus DPP-4 inhibitor versus metformin plus sulfonylurea combination therapy. The pooled RR estimates (95% CI) were 0.58 (0.41–0.82), I2 = 0, P = .002 and .72 (0.59–0.87), I2 = 70.7%, P = .001, respectively. The RRs of CVD mortality and all-cause mortality were statistically significant for association with the combination therapy of metformin plus DPP-4 inhibitor versus metformin plus sulfonylurea. These findings indicated that DPP-4 inhibitor versus sulfonylurea can lower the risk of CVD mortality and all-cause mortality in patients with T2DM. By excluding the study by Kannan et al,[16] sensitivity analysis of all-cause mortality was performed in which the outcome was inferior to the others. With the heterogeneity becoming small (I2 = 0%), the pooled estimate was 0.65 (0.59–0.72), P < .01 (Fig. 6). Statistically, there were significant differences between metformin plus DPP-4 inhibitor combination therapy and metformin plus sulfonylurea combination therapy. The outcome was relatively stable.

Figure 5.

Figure 5

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Forest plot: relative risk (RR) estimates and 95% confidence intervals (CIs) for cardiovascular mortality (A) and all-cause mortality (B) associated with the combination therapy of metformin plus DPP-4 inhibitor versus metformin plus sulfonylurea by study and pooled along with proportion of events for each outcome.

Figure 6.

Figure 6

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Forest plot: relative risk (RR) estimates and 95% confidence intervals (CIs) for cardiovascular mortality associated with the combination therapy of metformin plus DPP-4 inhibitor versus metformin plus sulfonylurea, excluding the study by Kannan et al and pooled along with proportion of events for each outcome. DPP-4 = dipeptidyl peptidase-4 inhibitors.

4. Discussion

T2DM affects a substantial and increasing number of people around the world.[15–17] As it is a progressive pathological process, many patients choose oral antihyperglycemic agents to obtain normal glycemic levels. For example, combination therapy of metformin plus sulfonylurea is the second step for T2DM patients in the recommended treatment process.[18] Nevertheless, based on the evidence, it is easy to see the beneficial effect of good glycemic control on the progression of microvascular complications in T2DM.[19–21] In addition, there has been an increasing incidence of cardiovascular events, and the majority of T2DM patients die from cardiovascular-related disease.[22] In previous retrospective cohort studies and meta-analyses, sulfonylurea monotherapy relative to metformin or metformin plus sulfonylurea combination therapy increased the overall mortality risk and CVD in patients suffering from T2DM.[23–25]

As hormones are released in response to changing glucose levels, endogenous glucagonlike peptide-1 and glucose-dependent insulinotropic polypeptide levels are enhanced, which is how DPP-4 inhibitors work. Evidence has shown that the use of DPP-4 inhibitors decreases the risk of cardiovascular events.[26,27] In addition, a recent meta-analysis has indicated that the combination therapy of metformin plus DPP-4 inhibitor significantly decreases the risks of CVD, cardiovascular mortality, and all-cause mortality in T2DM patients.

Combination therapy of metformin plus DPP-4 inhibitor significantly lowered the RR of nonfatal cardiovascular events, cardiovascular mortality, and all-cause mortality, compared with the combination of metformin plus sulfonylurea. However, there was no significant difference for fatal cardiovascular events between the 2 groups.[6,8] Based on these results, it is easy to understand the inconclusive outcomes of many large clinical studies comparing the studies of DPP-4 inhibitors and sulfonylureas on nonfatal cardiovascular events, CVD fatality, and all-cause mortality in T2DM patients, while the fatal cardiovascular events remain obscure.

In our analysis, from a statistical perspective, heterogeneity was significant across outcomes. After ruling out the study by Kannan et al,[16] with an outcome that was inferior, the result, with a small heterogeneity (I2 = 0%), becomes stable. According to the study by Kannan et al,[16] there is a great risk of congestive heart failure among users of metformin plus DPP-4 inhibitor, compared with metformin plus sulfonylurea. Moreover, regarding cardiovascular risk reduction, the combination therapy of metformin plus DPP-4 inhibitor was not better than metformin plus sulfonylurea. A potential explanation may be that the study had many limitations. If it was not accurately written down in the electronic health record by the healthcare providers in the USA, no events or prescriptions that occurred beyond the health system in the USA were included in the study. In addition, the study included patients such as those who had the greatest risk for heart failure hospitalization, those who suffered from an existing diagnosis of heart failure, those who had elevated levels of N-terminal prohormone brain natriuretic peptide at baseline, and those with an estimated glomerular filtration rate < 60 mL/min.

There are some limitations confronting the meta-analysis conducted in this report. First, some studies were not randomized controlled trials. Second, there were not ample studies presented in the meta-analysis. Third, we failed to mention the data of studies published only in abstract form (and some additional studies) because it was impossible to conduct a thorough analysis. Finally, some studies did not describe the duration of T2DM in patients or the monitoring index of blood glucose (A1C). These reasons are likely a source of prejudice. It is obvious that we need to carry out more trials that are highly qualified, well-designed, randomized, controlled, multicentered, and adequately powered to command the standards of therapy for T2DM with metformin plus DPP-4 inhibitor or metformin plus sulfonylurea to decrease the risk of cardiovascular events, CVD mortality, and all-cause fatality.

In conclusion, our meta-analysis showed that the combination therapy of metformin plus DPP-4 inhibitor significantly lowered the RR of nonfatal cardiovascular events, CVD fatality, as well as all-cause mortality, compared with the use of metformin plus sulfonylurea. However, there were no significant differences in terms of fatal cardiovascular events (e.g., heart failure) between the 2 groups, indicating that T2DM patients who are at high risk of cardiovascular events may use metformin plus DPP-4 inhibitor instead of metformin plus sulfonylurea to decrease the risk of cardiovascular events as well as CVD mortality. Obviously, more studies should be carried out to evaluate how combination therapy of metformin plus DPP-4 inhibitor versus metformin plus sulfonylurea is associated with cardiovascular events, cardiovascular mortality, and/or all-cause mortality.

Footnotes

Abbreviations: CI = confidence interval, CVD = cardiovascular disease, DPP-4 = dipeptidyl peptidase-4, MET = metformin, NICE = National Institute for Health and Care Excellence, RCT = randomised controlled trial, RR = relative risk, SU = sulfonylureas, T2DM = type 2 diabetes mellitus.

If accepted, QZ will handle the production process.

This work was supported by the State Science and Technology Support Program of China (2012BAI37B04).

The authors have no conflicts of interest to disclose.

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