Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2019 Mar;56(3):331-339.
doi: 10.1007/s00592-018-1253-5. Epub 2018 Nov 19.

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

Lorenzo M Vetrone  1   2 , Francesco Zaccardi  3 , David R Webb  1 , Sam Seidu  1 , Nitin N Gholap  4 , Dario Pitocco  2 , Melanie J Davies  1 , Kamlesh Khunti  1
Affiliations
Meta-Analysis

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

Lorenzo M Vetrone et al. Acta Diabetol. 2019 Mar.

Abstract

Aims: To investigate cardiovascular disease and mortality trends in control arm participants of diabetes cardiovascular outcome trials (CVOTs).

Methods: We 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.

Results: 26 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).

Conclusions: In 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.

Keywords: Cardiovascular; Mortality; Randomised trials; Systematic review; Trend; Type 2 diabetes.

PubMed Disclaimer

Conflict of interest statement

Data access and sharing

Data and statistical codes are available on request from the corresponding author (FZ).

Conflict of interest

KK has acted as a consultant and speaker for Novartis, Novo Nordisk, Sanofi-Aventis, Lilly and Merck Sharp and Dohme. He has received grants in support of investigator and investigator initiated trials from Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Pfizer, Boehringer Ingelheim and Merck Sharp and Dohme. KK has received funds for research, honoraria for speaking at meetings and has served on advisory boards for Lilly, Sanofi-Aventis, Merck Sharp and Dohme and Novo Nordisk. MJD has acted as consultant, advisory board member and speaker for Novo Nordisk, Sanofi-Aventis, Lilly, Merck Sharp and Dohme, Boehringer Ingelheim, AstraZeneca and Janssen, an advisory board member for Servier and as a speaker for Mitsubishi Tanabe Pharma Corporation and Takeda Pharmaceuticals International Inc. She has received grants in support of investigator and investigator initiated trials from Novo Nordisk, Sanofi-Aventis, Lilly, Boehringer Ingelheim and Janssen. DRW has received grants in support of investigator-initiated studies and honoraria from Sanofi-Aventis and Novo Nordisk. SS has received honoraria for speaking at meetings and serving on Advisory Boards for Novartis, Novo Nordisk, Janssen, MSD, Lilly, and Boehringer Ingelheim. FZ has received honoraria for speaking at meetings for NAPP Pharmaceuticals. LMV, NNG, DP: no relevant conflict of interest.

Human and animal rights statement

This article does not contain any studies with human participants performed by any of the authors.

Informed consent

For this type of study, formal consent is not required.

Figures

Fig. 1
Fig. 1
Unadjusted outcome rates by calendar year. Each circle indicates a randomised controlled trial and its size is proportional to the inverse of rate variance. Shadow areas indicate 95% confidence interval
Fig. 2
Fig. 2
Outcome-specific rate ratios. Black and blue estimates indicate 5-year rate ratios for main and sensitivity analysis (excluding DEVOTE, TOSCA, HEART 2D), respectively. Major adverse cardiovascular events definitions are reported in Supplemental Table S3
See this image and copyright information in PMC

References

    1. Ogurtsova K, da Rocha Fernandes JD, Huang Y, et al. IDF Diabetes Atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract. 2017;128:40–50. doi: 10.1016/j.diabres.2017.03.024. - DOI - PubMed
    1. Rao Kondapally Seshasai S, Kaptoge S, Thompson A, et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 2011;364(9):829–841. doi: 10.1056/NEJMoa1008862. - DOI - PMC - PubMed
    1. Di Angelantonio E, Kaptoge S, Wormser D, et al. Association of cardiometabolic multimorbidity with mortality. JAMA. 2015;314(1):52–60. doi: 10.1001/jama.2015.7008. - DOI - PMC - PubMed
    1. Tancredi M, Rosengren A, Svensson AM, et al. Excess mortality among persons with type 2 diabetes. N Engl J Med. 2015;373(18):1720–1732. doi: 10.1056/NEJMoa1504347. - DOI - PubMed
    1. Simmons RK, Griffin SJ, Lauritzen T, Sandbaek A. Effect of screening for type 2 diabetes on risk of cardiovascular disease and mortality: a controlled trial among 139,075 individuals diagnosed with diabetes in Denmark between 2001 and 2009. Diabetologia. 2017;60(11):2192–2199. doi: 10.1007/s00125-017-4299-y. - DOI - PMC - PubMed

MeSH terms