Findings from a recently published meta-analysis of patients with pre-diabetes, with and without ASCVD, suggest an increased risk for premature death and cardiovascular events.
The term “pre-diabetes” has been the subject of debate, and the Centers for Disease Control and Prevention warn that the “pre” before diabetes is misleading.1 Numerous published studies and meta-analyses support the association between pre-diabetes and premature death and increased cardiovascular events.2 So why the need for additional studies? According to Cai and colleagues, “most of the previous studies had limited power to draw reliable conclusions”.3 To address this limitation, Cai and colleagues performed an updated meta-analysis of published studies, up to April 25, 2020. A total of 129 studies, with 10 million individuals, were included in this updated analysis. Individuals in the analysis were from either the general population or a population with a history of atherosclerotic cardiovascular disease (ASCVD).3 In a previous meta-analysis of 53 studies of more than 1.6 million people from the general population, Cai and colleagues found an increased risk of cardiovascular disease and death; however, this original analysis did not include individuals with a history of ASCVD.2
Electronic databases were searched to identify eligible prospective cohort studies and post hoc analysis of clinical trials. Pre-diabetes was defined as any or all of the following: an impaired fasting plasma glucose (IFG) according to the American Diabetes Association (ADA) guidelines (100-125 mg/dL) or the World Health Organization criteria of IFG (110-125 mg /dL), a 2-hour impaired glucose tolerance (140-199 mg/dL) or an elevated A1C according to the ADA (5.7-6.4%) or International Expert Committee guidelines (6.0%-6.4%). Primary outcomes of interest were all-cause mortality and composite cardiovascular events, and secondary outcomes were coronary heart disease and stroke risks. Relative risk (RR) and absolute risk difference, expressed as events per 10,000 person-years, were calculated using the median risk of euglycemic patients’ outcomes as the comparator.3
Studies in the analysis were primarily from Europe, Asia, and North America, and the median follow-up time was 9.8 years. In the general population studies, pre-diabetes was associated with an increased RR of 13% for death due to any cause, 15% for composite cardiovascular disease, 16% for coronary heart disease, and 14% for stroke. In these studies the absolute risk for patients with pre-diabetes, compared to those without, for the primary and secondary outcomes of interest were: 7.36 (95 % CI 9.6 to 12.5) for death due to any cause, 8.75 (95% CI 6.4 to 10.5) for composite cardiovascular disease, 6.59 (95% CI 4.5 to 8.7) for coronary heart disease and 3.68 (95% CI 2.1 to 5.3) per 10,000 person-years.3
In studies that included patients with a history of ASCVD, pre-diabetes was associated with an increased RR of 36% for all-cause death, 37% for cardiovascular disease, 15% for coronary heart disease, and a non-significant 5% for stroke. The absolute increased risk in patients with ASCVD and pre-diabetes, compared to those without pre-diabetes, for the primary and secondary endpoints, were: all-cause death: 66 (95% CI 39 to 99), composite cardiovascular disease: 190 (95% CI 118 to 272), coronary heart disease: 40.62 (5.4 to 78.5) and stroke: 8.54 (-32.4 to 61.5), per 10,000 person-years.3
In the general population, when pre-diabetes was defined using impaired glucose tolerance compared to impaired fasting plasma glucose, there was a significantly increased risk of death and stroke. However, this association was not observed in patients with a history of ASCVD. The possibility that the increased risks observed in the study were not due to pre-diabetes, but rather, diabetes progression, needs to be considered when evaluating these results.
These findings suggest that when it comes to pre-diabetes and premature death or cardiovascular events, there is no gray zone. Previous studies have established that pre-diabetes places patients at an increased risk of premature death and cardiovascular events. The expansion of the eligibility criteria in this updated analysis, to include individuals with ASCVD, provides new and valuable insight into the even higher risk of death and cardiovascular disease in this population.
- Patients with pre-diabetes are at an increased risk of premature death and cardiovascular events.
- Patients with pre-diabetes and ASCVD are at an even higher risk of death and future cardiovascular events.
- Early identification and treatment of patients with pre-diabetes, either with or without ASCVD, is essential to ensure they do not fall into the gray zone and remain at risk for premature death and cardiovascular events.
- The Surprising Truth About Prediabetes. Centers for Disease Control and Prevention. https://www.cdc.gov/diabetes/library/features/truth-about-prediabetes.html. Last reviewed: June 11, 2020. Accessed July 23, 2020
- Huang, Yuli, et al. “Association between pre-diabetes and risk of cardiovascular disease and all-cause mortality: systematic review and meta-analysis.” BMJ vol.355 (2016): i5953. doi: https://doi.org/10.1136/bmj.i5953
- Cai, Xiaoyan, et al. “Association between pre-diabetes and risk of all-cause mortality and cardiovascular disease: an updated meta-analysis.” BMJ vol. 370 (2020):m2297. doi: https://doi.org/10.1136/bmj.m2297
Louise Brown, PharmD Candidate, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences