Cardiovascular and mortality events in type 2 diabetes cardiovascular outcomes trials: a systematic review with trend analysis

Lorenzo M. Vetrone,Nitin N. Gholap,Kamlesh Khunti,Melanie J. Davies,Francesco Zaccardi,David R. Webb,Dario Pitocco,Sam Seidu

doi:10.1007/s00592-018-1253-5

Lorenzo M. Vetrone, Nitin N. Gholap + Show 6 more

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https://doi.org/10.1007/s00592-018-1253-5

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Abstract

AimsTo investigate cardiovascular disease and mortality trends in control arm participants of diabetes cardiovascular outcome trials (CVOTs).MethodsWe electronically searched CVOTs published before October 2017. Data on all-cause mortality, cardiovascular mortality and events, and baseline characteristics were collected, along with study calendar years. Trends were estimated using negative binomial regressions and reported as rate ratio (RR) per 5-year intervals.Results26 CVOTs, conducted from 1961 to 2015, included 86788 participants with 6543 all-cause deaths, 3265 cardiovascular deaths, and 7657 3-point major adverse cardiovascular events (3-P MACE; combined endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke). In unadjusted analysis, there was an increasing trend for 3-P MACE rates over time (5-year RR 1.57; 95% CI 1.34, 1.84); a small increasing trend for cardiovascular disease mortality rates (1.13; 1.01, 1.26); and stable rates for all-cause death. Adjusting for age, sex, previous myocardial infarction, and diabetes duration, there was no evidence of trends for 3-P MACE or cardiovascular disease mortality rates, while reducing rates were observed for nonfatal myocardial infarction (5-year RR: 0.72; 0.54, 0.96), total stroke (0.76; 0.66, 0.88), and nonfatal stroke (0.60; 0.43, 0.82).ConclusionsIn contrast to real-world data, there was no evidence of an improvement in all-cause and cardiovascular mortality in type 2 diabetes participants included in control arms of randomised clinical trials across 5 decades. Further studies should investigate whether and how dissimilarities in populations, procedures, and assessments of exposures and outcomes explain the differences between real-world setting and clinical trials.

Highlights

Type 2 diabetes mellitus (T2DM) is a complex cardiometabolic disorder affecting approximately 8.5% of the global population [1]
The characteristics of the included randomised controlled trials (RCTs) are shown in Table 1: they span 5 decades, from 1966 to 2015, and enrolled a total of 86,788 participants with T2DM; most studies (21/26, 80.7%) were conducted after year 2000
RCTs reported several outcomes (Table 2 and Table S2): data were complete for all-cause mortality (26 RCTs, 86,788 participants, 6543 events), followed by cardiovascular disease mortality (19 RCTs, 71,405 participants, 3265 events), total stroke, and 3-point major adverse cardiovascular events (3-P MACE definitions are reported in Table S3; 15 RCTs, 71,641 participants, 7657 events)

Summary

Introduction

Type 2 diabetes mellitus (T2DM) is a complex cardiometabolic disorder affecting approximately 8.5% of the global population [1]. Elevated plasma glucose concentration is consistently and directly associated with cardiovascular complications and mortality in multiple, large epidemiological studies in people with T2DM; yet, whether treatment of hyperglycaemia and in particular intensive glucose control translates into a lower risk of cardiovascular disease and mortality remains uncertain. To assure high internal validity and reduce the variation in baseline risk factors, RCTs use strict inclusion criteria and commonly exclude very ill patients. These factors may potentially contribute to differences between realworld and RCTs in terms of both treatment effects and absolute risk of disease-related outcomes. In contrast to “real-world” evidence, a systematic assessment of trends of diabetes-related outcomes from randomised controlled trials (RCTs) is lacking [11,12,13]. Recent systematic evaluations included only RCTs published up to March 2011 [13], while the number of available RCTs reporting cardiovascular outcomes has increased significantly since 2008, when the US Food and Drug Administration (FDA) mandated inclusion of cardiovascular outcomes trials (CVOTs) in safety assessments of newer glucose-lowering drugs [14]

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