LEADER 7: cardiovascular risk profiles of US and European participants in the LEADER diabetes trial differ

The Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial [1] is one of at least 16 cardiovascular outcome trials in type 2 diabetes (T2D) that will report before 2020 [2]. Driven by regulatory requirements to demonstrate cardiovascular safety, trial sample sizes are large. To recruit 10‒20,000 participants per trial, there are 17–27 countries per trial, resulting in a wider range of racial and ethnic participation, as well as greater variation in clinical practice patterns than in previous T2D studies [2]. The clinical usefulness of trial data obtained for a particular clinician or policy-maker depends on how well the trial population mirrors the patients in that clinician’s practice, or the population for whom the policy is developed. This external validity is determined by inclusion criteria, but also by patients’ enrolment, retention, and protocol adherence. The age distribution of trial participants in seven large diabetes trials often did not reflect that of a contemporary British T2D patient population [3]. Most ongoing diabetes cardiovascular outcome trials are being conducted in populations with high cardiovascular risk with a long history of T2D [2]. Women and ethnic minorities are under-represented in US-based clinical trials, although these groups have disproportionally higher rates of chronic diseases [4]. The generalizability of results even from well-performed trials may be jeopardized when participants differ from the clinical population with respect to attributes that modify treatment [5]. In a multivariate model, female sex, renal insufficiency, and heart failure were significant predictors of not participating in a trial [6]. Such clinical factors are important because they may modify treatment effects. The table of baseline characteristics in trial reports should focus on baseline factors associated with primary outcomes [7].

Patient enrolment is likely to be dependent on the specific types of investigator practices (generalist, diabetologist, cardiologist, nephrologist, etc.) and on the healthcare systems they operate within. A UK study suggests that selection of study sites should aim to represent the general medical management of T2D patients [8]. It might be questioned whether such a strategy is economically and logistically possible in large global trials.

We seek to examine whether there are important baseline differences in cardiovascular risk markers among LEADER participants enrolled in the US and Europe. This study of these two populations was prompted by the substantial differences between the US and Europe, for example with respect to demographics; cultural norms regarding diet, activity, and other health behaviors; prevailing treatment guidelines for glycemia, blood pressure (BP), lipids, and cardiovascular management; and funding and nature of healthcare systems [9, 10]. We examined baseline demographic and clinical characteristics of LEADER participants in the US and Europe without a priori hypotheses. Such an exploratory investigation may generate hypotheses about possible heterogeneity [11], and be informative for potential post hoc analyses [11, 12].

This study identified relevant differences in baseline cardiovascular risk profiles between European and US participants in the LEADER trial. These differences should be considered in the analysis and reporting of the trial results.

LEADER aims to formally assess the cardiovascular safety of liraglutide, as reflected in the number of cardiovascular events. The trial population consists of people with/without history of CVD. The large number of subjects, as well as the number of study sites, will ensure the results reflect wide clinical practice, and thus the robustness of the primary results. However, whether liraglutide is noninferior to placebo [1] in subgroups will at least partially depend on the baseline risk of the participants. The European and US populations in LEADER differed in many factors related to cardiovascular risk, including race, BMI, HbA1c, SBP and DBP, ventricular dysfunction, and, in the group without prior CVD, albuminuria. In some aspects, US participants may have a lower cardiovascular risk because of their substantially lower BP level and lower prevalence of left ventricular dysfunction, but this could be counteracted by higher cardiovascular risk because of higher BMI and HbA1c. The baseline differences identified should be explored in relation to the overall trial results, once reported. Specifically, testing for heterogeneity of the treatment effect and interactions between subgroups would be needed to evaluate whether these differences impact upon the generalizability of the overall trial findings. Thus, these baseline findings should be interpreted with caution, but may inform additional analyses. Calculating an individual’s 10-year CVD risk in people without prior CVD may also help identify which patients benefit most from the treatments under study [15, 16].

Regional differences are not unique to LEADER: they probably exist in all global trials, and in cardiovascular outcome trials in diabetes in particular. The analysis in this study provides more detail on potential relevant differences, and hence will support interpretation of the final results. The implications of these data, which show differences related to baseline cardiovascular risk management between US and European participants, may also be relevant in shaping future trial designs with similar populations. Such trial designs will need to account for factors pertaining to cardiovascular risk.

Strengths of this study include the large patient groups involved and investigation of the role of the ‘region’, independently from patient-related anthropometric and disease-related factors. Region, i.e. Europe or US (a cultural-, socio-economic-, and healthcare-related characteristic), was the most important factor associated with participants achieving HbA1c, BP, and LDL targets. Many of the baseline differences between the US and Europe appear driven by variation in regional targets for cardiovascular risk management. However, the role of ‘region’ may not only be determined by guidelines and physician prescription patterns, but also the sites that enrolled patients, the way they did so, and patient‒physician relationships. A recent systematic review and meta-analysis of randomized controlled trials demonstrated that intensive glycemic control in patients with T2D was associated with increases in all-cause mortality, cardiovascular mortality, and severe hypoglycemia in study populations from North America compared with the rest of the world [17]. Its authors emphasized the need for further investigation into these findings [17]. The choice of participating centers can also influence the generalizability of trial results. For example, among >55,000 high-risk patients presenting with non-ST-segment elevation acute coronary syndrome at 443 US hospitals, 1397 (2.5 %) patients were enrolled in a clinical trial. The latter were more often cared for by cardiologists at hospitals capable of catheter-based and surgical revascularization—which might explain the high rates of revascularization among clinical trial patients [6]. Such discrepancies in care and patient characteristics would suggest that the data from this and similar cardiovascular studies cannot be extrapolated to the broad type 2 diabetes population. In the global Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin (TECOS), regional differences were noted, with lower BP and cholesterol levels in US participants, compared to participants both from western and eastern Europe. Treatment target achievement was also associated with the type of prior vascular disease [18]. Therefore, region-specific data about the centers that enrolled patients (for example, academic sites, rural sites etc.), and region-specific loss-to-follow-up data would enable readers to judge the applicability of the trial results for their practice population.

LEADER was undertaken to assess the cardiovascular safety of liraglutide. A large set of exploratory subgroup analyses have been pre-specified to assess the effect of (among others) sex, BMI, region, cardiovascular risk, chronic heart failure, and severe chronic renal failure on the primary composite endpoint [1]. The present study demonstrates the relevance of these planned subgroup analyses and of evaluating any heterogeneity in outcomes. In this respect, it could also be relevant to present detailed data about sites of enrolment and loss to follow-up. Finally, patient-level meta-analysis of the CVD trials underway would allow for deeper exploration of these issues, as sufficient sample size of many subgroups would be available [19].

This study demonstrated important baseline differences between US and European participants in the LEADER trial. These differences may be the result of regional variations in targets for cardiovascular risk factor management. These factors should be considered in the analysis and reporting of the trial results and may also be relevant for potential post hoc investigations.