The Combination of DPP-4 Inhibitors Versus Sulfonylureas with Metformin After Failure of First-line Treatment in the Risk for Major Cardiovascular Events and Death

doi:10.1016/j.jcjd.2015.02.002

Canadian Journal of Diabetes

Volume 39, Issue 5, October 2015, Pages 383-389

https://doi.org/10.1016/j.jcjd.2015.02.002 Get rights and content

Abstract

Objective

To determine whether the combination of dipeptidyl-peptidase 4 (DPP-4) inhibitors vs. sulfonylureas with metformin after failure of first-line treatment is associated with a decreased risk for major adverse cardiovascular events (myocardial infarction and stroke) and for all-cause mortality.

Method

Using the UK Clinical Practice Research Datalink, a cohort of patients newly treated with metformin or sulfonylurea monotherapy between January 1, 1988, and December 31, 2011, was identified and was followed until December 31, 2012. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models to compare the DPP-4 inhibitor-metformin combination to the sulfonylurea-metformin combination so as to study the risk for a composite endpoint consisting of myocardial infarction, stroke and all-cause mortality. The models were adjusted for high-dimensional propensity score deciles.

Results

The cohort consisted of 11,807 patients that included 2286 on a DPP-4 inhibitor-metformin combination and 9521 on a sulfonylurea-metformin combination. The crude incidence rates (95% CIs) of the composite endpoint were 1.2% (0.8% to 1.7%) and 2.2% (1.9% to 2.5%) per year for the DPP-4 inhibitor-metformin and sulfonylurea-metformin combinations, respectively. In the high-dimensional propensity score-adjusted model, the use of the DPP-4 inhibitor-metformin combination was associated with a 38% decreased risk for the composite endpoint (adjusted HR: 0.62; 95% CI 0.40 to 0.98), compared with the sulfonylurea-metformin combination.

Conclusions

The use of a DPP-4 inhibitor combination with metformin, compared with a sulfonylurea-metformin combination, was associated with decreased risks for major cardiovascular events and all-cause mortality.

Résumé

Objectif

Déterminer si la combinaison des inhibiteurs de la dipeptidylpeptidase-4 (DPP-4) vs les sulfonylurées avec la metformine après l’échec du traitement de première intention est associée à une diminution du risque d’événements cardiovasculaires majeurs (infarctus du myocarde et accident vasculaire cérébral) et de la mortalité toutes causes confondues.

Méthodes

À l’aide du registre britannique UK Clinical Practice Research Datalink, une cohorte de patients récemment traités par la metformine ou une sulfonylurée en monothérapie entre le 1^er janvier 1998 et le 31 décembre 2011 a été déterminée et a été suivie jusqu’au 31 décembre 2012. Les rapports de risque (RR) et les intervalles de confiance (IC) à 95 % ont été estimés à l’aide des modèles de risques proportionnels de Cox pour comparer la combinaison de la metformine et de l’inhibiteur DPP-4 à la combinaison de la metformine et de la sulfonylurée afin d’étudier le risque de survenue du critère de jugement composite comportant l’infarctus du myocarde, l’accident vasculaire cérébral et la mortalité toutes causes confondues. Les modèles ont été ajustés selon les déciles du score de propension dimensionnel élevé.

Résultats

La cohorte comptait 11 807 patients dont 2286 sujets prenaient la combinaison de metformine et de DPP-4 et 9521 sujets prenaient la combinaison de metformine et de sulfonylurée. Les taux d’incidence bruts (les IC à 95 %) du critère de jugement composite étaient respectivement de 1,2 % (0,8 % à 1,7 %) et de 2,2 % (1,9 % à 2,5 %) par année pour la combinaison de metformine et de l’inhibiteur DPP-4 et la combinaison de metformine et de sulfonylurée. Dans le modèle ajusté du score de propension dimensionnel élevé, l’utilisation de la combinaison de metformine et de l’inhibiteur DPP-4 était associée à une diminution du risque de 38 % pour le critère de jugement composite (RR ajusté : 0,62; IC à 95 %, 0,40 à 0,98) comparativement à la combinaison de metformine et de sulfonylurée.

Conclusions

L’utilisation de la combinaison de la metformine et d’un inhibiteur DPP-4 comparativement à la combinaison de la metformine et d’une sulfonylurée était associée à la diminution des risques d’événements cardiovasculaires majeurs et de la mortalité toutes causes confondues.

Introduction

Current treatment guidelines recommend the use of metformin as the initial therapy for type 2 diabetes 1, 2, 3. However, failure to attain target glycemic control (glycated hemoglobin (A1C) <53 mmol/mol) occurs at a rate of 5% to 10% per year with this initial therapy 4, 5, 6. In these situations, a second-line agent is often given as an add-on therapy to metformin to further improve glycemic control. There are a number of available second-line agents, but there are uncertainties as to which agent provides the optimal cardiovascular benefit in the treatment of type 2 diabetes.

Until recently, sulfonylureas have been the preferred add-on second-line agents to be used with metformin, mainly because of their lower cost. However, sulfonylureas have been associated with an increased risk for hypoglycemia, weight gain and cardiovascular risks 7, 8, 9. Because of these pitfalls, novel agents such as incretin-based therapies (i.e. dipeptidyl-peptidase 4 [DPP-4] inhibitors and glucagon-like peptide -1 [GLP-1] analogues) are now being recommended as second-line or third-line therapies, according to the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) guidelines (1) due to their decreased risks for inducing hypoglycemia and weight gain. To our knowledge, 2 observational studies have been performed that compared the effectiveness of the DPP-4 inhibitor-metformin combination to the sulfonylurea-metformin combination on cardiovascular and mortality outcomes (10). However the results of these studies are conflicting.

Thus, given the uncertainties related to the optimal choice of a second-line add-on therapy to metformin, we conducted a large population-based study to determine whether the add-on of DPP-4 inhibitors vs. sulfonylureas to metformin is associated with a decreased risk for major adverse cardiovascular events (myocardial infarction [MI] and stroke) and all-cause mortality.

Section snippets

Data sources

This study was conducted by using the United Kingdom Clinical Practice Research Datalink (CPRD). The CPRD is a large electronic database that contains data concerning more than 13 million individuals enrolled in over 680 general practices, including diagnoses and prescription information, that have been shown to have good accuracy in a number of validation studies 11, 12. For the purposes of a sensitivity analysis (described below), we linked the CPRD to the Hospital Episode Statistics (HES)

Results

A total of 2286 patients with DDP-4 inhibitor-metformin combinations and 9521 patients with sulfonylurea-metformin combinations met the study’s inclusion criteria (Figure 1).The baseline characteristics of the exposure groups are shown in Table 1. Compared to the sulfonylurea-metformin combination, users of the DPP-4 inhibitor-metformin combination were slightly younger, more likely to be overweight or obese, and less likely to have A1C levels >86 mmol/mol.

Figure 2 presents the crude cumulative

Discussion

The results of this large population-based study indicate that DPP-4 inhibitors, when used as second-line agents in combination with metformin, are associated with a 38% decreased risk for major cardiovascular events and all-cause mortality, compared to sulfonylurea-metformin combinations. These results remained consistent in the secondary and sensitivity analyses. The results of this study suggest that DPP-4 inhibitors may be a better add-on to first-line treatment than standard sulfonylurea

Conclusion

In summary, the results of this study indicate that compared to sulfonylurea-metformin combinations, the use of DPP-4 inhibitor-metformin combinations is associated with decreased risk for major cardiovascular events and all-cause mortality. These results suggest that DPP-4 inhibitors may be better second-line agents in the treatment of type 2 diabetes compared to sulfonylureas. Additional studies, including randomized controlled trials, will be necessary to confirm this result so as to further

Acknowledgements

Dr. Laurent Azoulay is the recipient of a Chercheur-Boursier career award from the Fonds de recherche du Québec, Santé.

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Cited by (28)

The efficacy and safety of dipeptidyl peptidase-4 inhibitors compared to other oral glucose-lowering medications in the treatment of type 2 diabetes
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Citation Excerpt :
In other words, the combination of metformin plus DPP-4i was associated with a lower incidence of all-cause mortality, CV mortality, and the 3-point MACE, in comparison with metformin plus sulphonylurea [85]. Similar findings have emerged from the UK Clinical Practice Research Datalink (CPRD), which demonstrated a reduction in MACE and all-cause mortality for subjects under treatment with metformin and DPP-4i versus the use of metformin with sulphonylurea [86,87]. The Korean Health Insurance Database Study showed that DPP-4is combined with metformin decreased CVD risk compared to sulphonylureas added to metformin in T2DM patients [88].
The dipeptidyl peptidase-4 inhibitors (DPP-4is), which belong to the class of incretin-based medications, are recommended as second or third-line therapies in guidelines for the management of type 2 diabetes mellitus. They have a favorable drug tolerability and safety profile compared to other glucose-lowering agents.
This review discusses data concerning the use of DPP-4is and their cardiovascular profile, and gives an updated comparison with the other oral glucose-lowering medications with regards to safety and efficacy. Currently available original studies, abstracts, reviews articles, systematic reviews and meta-analyses were included in the review.
DPP4is are moderately efficient in decreasing the HbA1c by an average of 0.5% as monotherapy, and 1.0% in combination therapy with other drugs. They have a good tolerability and safety profile compared to other glucose-lowering drugs. However, there are possible risks pertaining to acute pancreatitis and pancreatic cancer.
Cardiovascular outcome trials thus far have proven the cardiovascular safety for ischemic events in patients treated with sitagliptin, saxagliptin, alogliptin, linagliptin and vildagliptin. Data showing increased rate of hospitalisation in the case of saxagliptin did not seem to be a class effect.
Cardiovascular safety of DPP-4 inhibitors compared with sulphonylureas: Results of randomized controlled trials and observational studies
2018, Diabetes and Metabolism
Citation Excerpt :
Data from the UK Clinical Practice Research Datalink (CPRD) showed reductions in MACE and all-cause mortality for patients treated with metformin plus DPP-4i vs metformin plus SU (Table 3) [55]. These data were confirmed by a further publication (also using the CPRD) reporting significantly decreased risks for MACE and all-cause mortality in patients treated with DPP-4is compared with SUs (Table 3) [56]. In a retrospective cohort study using UK primary-care data linked to hospitalization and mortality records, the adjusted hazard ratio (HR) for an extended composite of MACE was 0.78 (95% CI: 0.55–1.11) for the metformin plus DPP-4i regimen compared with the metformin plus SU regimen [57].
After failure of metformin monotherapy, another glucose-lowering agent should be added to improve glucose control. The clinician has several pharmacological choices, including the addition of a sulphonylurea (SU) or a dipeptidyl peptidase-4 inhibitor (DPP-4i). While the cardiovascular safety of SUs remains a matter of controversy, DPP-4is have proven their non-inferiority vs placebo in recent cardiovascular (CV) outcome trials. In the absence of a head-to-head CV outcome trial—the CAROLINA, comparing linagliptin with glimepiride, is still ongoing—only indirect information can be found in the literature to compare CV outcomes (major CV events, myocardial infarction, ischaemic stroke, CV death and all-cause mortality) in patients with type 2 diabetes mellitus (T2DM) treated with SUs or DPP-4is. Thus, this comprehensive review summarizes the CV outcomes (excluding heart failure) reported in meta-analyses of randomized controlled trials (RCTs) of SUs vs placebo or other glucose-lowering agents, DPP-4is vs placebo or other glucose-lowering agents and SUs vs DPP-4is in phase-II/III studies. Also, the results of observational studies reporting CV events in patients treated with either SUs or DPP-4is have been carefully examined. Overall, the CV safety of SUs appears to be poorer than that of DPP-4is in both RCTs and cohort studies. However, the results are somewhat disparate, and such heterogeneity may be explained by different patient characteristics across studies, but also perhaps by differences between various molecules in each pharmacological class. In particular, some doubt about a class effect affecting SU CV safety has been raised. The results of CAROLINA are expected to shed more light on SU CV concerns, especially compared with DPP-4is.
Impact of glucose-lowering therapies on risk of stroke in type 2 diabetes
2017, Diabetes and Metabolism
Citation Excerpt :
In a US population-based case control study of users of long-acting insulin, current use of SU compared with never use was associated with a greater risk of MI, but only a trend towards higher risk of stroke (Table 1) [15]. Several recent observational studies comparing SUs with DPP-4 inhibitors in T2D patients reported a greater incidence of pooled major cardiovascular events with SUs, but lacked separate data for MIs and stroke events [25–27]. However, no deleterious influence of SUs on stroke severity and in-hospital outcomes for stroke patients has been reported [28].
Patients with type 2 diabetes (T2D) have an increased risk of stroke compared with people without diabetes. However, the effects of glucose-lowering drugs on risk of ischaemic stroke in T2D have been less extensively investigated than in coronary heart disease. Some evidence, including the UKPDS, has suggested a reduced risk of stroke with metformin, although the number of studies is limited. Inhibition of the K_ATP channels increases ischaemic brain lesions in animals. This is in agreement with a recent meta-analysis showing an increased risk of stroke with sulphonylureas vs. various comparators as both mono- and combination therapy. Pioglitazone can prevent recurrence of stroke in patients with previous stroke, as already shown in PROactive, although results are less clear for first strokes. As for DPP-4 inhibitors, there was a non-significant trend towards benefit for stroke, whereas a possible increased risk of stroke with SGLT2 inhibitors—and in particular, empagliflozin in the EMPA-REG OUTCOME trial—has been suggested and requires clarification. Experimental results support a potential protective effect of GLP-1 receptor agonists against stroke that has, at least in part, been translated to clinical benefits in T2D patients in the LEADER and SUSTAIN-6 trials. Further interventional studies are now warranted to confirm the effects of glucose-lowering agents on risk of stroke in patients with T2D. In summary, the effects of antidiabetic drugs on risk of stroke appear to be heterogeneous, with some therapies (pioglitazone, GLP-1 receptor agonists) conferring possible protection against ischaemic stroke, other classes showing a neutral impact (DPP-4 inhibitors, insulin) and some glucose-lowering agents being associated with an increased risk of stroke (sulphonylureas, possibly SGLT2 inhibitors, high-dose insulin in the presence of insulin resistance).
Comparative risk for cardiovascular diseases of dipeptidyl peptidase-4 inhibitors vs. sulfonylureas in combination with metformin: Results of a two-phase study
2016, Journal of Diabetes and its Complications
Citation Excerpt :
In the secondary analyses, we observed a non-significantly reduced cardiovascular risk for the single DPP-4 inhibitors saxagliptin and vildagliptin compared to sitagliptin. The results are in line with the study based on CPRD which reported no difference between users of DPP-4 inhibitors compared to sulfonylureas after failure of first-line therapy with metformin regarding the risk of a major cardiovascular event (Yu et al., 2015). However, although not significant, the 26% decrease in risk was higher compared to the 17% decrease in risk observed in our study.
The aim was to assess whether the use of additional data from the Disease Management Program (DMP) diabetes mellitus type 2 to minimize the potential for residual confounding will alter the estimated risk of either myocardial infarction, ischemic stroke or heart failure in patients with type 2 diabetes using sulfonylureas compared to dipeptidyl peptidase-4 (DPP-4) inhibitors in addition to metformin based on routine health care data.
We conducted a nested two-phase case–control study using claims data of one German health insurance from 2004 to 2013 (phase 1) and data of the DMP from 2010 to 2013 (phase 2). Adjusted odds ratios (ORs) for the combined cardiovascular event myocardial infarction, ischemic stroke or heart failure were calculated using a two-phase logistic regression.
Phase 1 comprised 3179 patients (289 cases; 2890 controls) and phase 2 comprised 1968 patients (168 cases; 1800 controls). We observed an adjusted OR of 0.83 for the combined cardiovascular event (95% CI: 0.61–1.13).
We observed a non-significantly reduced risk for cardiovascular diseases in patients using DPP-4 inhibitors compared to sulfonylureas in addition to metformin. This finding was not altered by the inclusion of additional information of the DMP in the analysis. However, due to the low power of this study, further studies are needed to reproduce our findings.
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Original ResearchThe Combination of DPP-4 Inhibitors Versus Sulfonylureas with Metformin After Failure of First-line Treatment in the Risk for Major Cardiovascular Events and Death

Abstract

Objective

Method

Results

Conclusions

Résumé

Objectif

Méthodes

Résultats

Conclusions

Introduction

Section snippets

Data sources

Results

Discussion

Conclusion

Acknowledgements

Am J Med

Management of hyperglycemia in type 2 diabetes: A patient-centered approach: Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

Diabetes Care

Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada: Pharmacologic management of type 2 diabetes

Can J Diabetes

(UKPDS) UKPDS. Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years

BMJ

Group UKPDS. Overview of 6 years' therapy of type II diabetes: A progressive disease

Diabetes

Group UPDS. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)

Lancet

Is there evidence that oral hypoglycemic agents reduce cardiovascular morbidity/mortality?

Yes. Diabetes Care

Sulfonylureas: Do we need to introspect safety again?

Expert Opin Drug Saf

Mortality among veterans with type 2 diabetes initiating metformin, sulfonylurea or rosiglitazone monotherapy

Diabetologia

What next after metformin? A retrospective evaluation of the outcome of second-line, glucose-lowering therapies in people with type 2 diabetes

J Clin Endocrinol Metabol

Validation of information recorded on general practitioner based computerised data resource in the United Kingdom

BMJ

Validity of diagnostic coding within the General Practice Research Database: A systematic review

Brit J Gen Pract

Systematic review of discharge coding accuracy

J Pub Health Med (Oxford)

Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus: A cohort study

Ann Intern Med

The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: Nested case-control study

BMJ

Association between first-line monotherapy with sulfonylurea versus metformin and risk of all-cause mortality and cardiovascular events: A retrospective, observational study

Diabetes, Obesity Metabol

Initial choice of oral glucose-lowering medication for diabetes mellitus: A patient-centered comparative effectiveness study

JAMA Intern Med

Original Research
The Combination of DPP-4 Inhibitors Versus Sulfonylureas with Metformin After Failure of First-line Treatment in the Risk for Major Cardiovascular Events and Death