Pre-Diabetes Increases Risk of CVD and All-Cause Mortality

Numerous complications associated with diabetes, including CVD (cardiovascular disease) and the risk of death, begin with pre-diabetes.

The American Diabetes Association defines pre-diabetes as a borderline glycemia measured by fasting plasma glucose (FPG) of 100-125 mg/dL, 2-h plasma glucose (2hPG) of 140–199 mg/dL, and HbA1c of 5.7–6.4%.

People with pre-diabetes have shown early stages of retinopathy, nephropathy, and neuropathy. Other disorders typically associated with diabetes have been observed in people with pre-diabetes, such as cardiovascular disease, periodontal disease, cognitive dysfunction, obstructive sleep apnea, metabolic syndrome, fatty liver, and cancer.

The Whitehall II cohort study found that people with HbA1c level consistent with pre-diabetes remained pre-diabetic or advanced to diabetic status within five years. However, people with FPG or 2hPG consistent with pre-diabetes could return to a status of normoglycemia, which was associated with reduced risk of CVD and mortality.

This raises the question: is pre-diabetes merely a risk factor, or is it a disease state?

An updated meta-analysis recently published in The BMJ aimed to evaluate the association between pre-diabetes and the risk of all-cause mortality and CVD, both in the general population and in patients with a history of atherosclerotic CVD.

The study looked into two questions:

• Is pre-diabetes associated with an increased risk of all-cause mortality and cardiovascular disease in the general population and in patients with a history of atherosclerotic cardiovascular disease?
• Are different definitions of pre-diabetes related to different prognoses?

A search through the electronic databases was performed from June 2019 till April 2020, where studies meeting specific criteria were included. Pre-diabetes was defined as impaired glucose tolerance, impaired fasting blood glucose according to both the ADA and WHO, and impaired HbA1c according to both the ADA and IEC.

Newcastle-Ottawa quality assessment scale was used to assess the selected studies’ quality, and they were also evaluated for whether they have been adequately adjusted for potential confounders.

The meta-analysis’s primary outcome was the risk of all-cause mortality and composite CV events in the general population and patients with atherosclerotic CVD.

The secondary outcome was the risk of coronary heart disease and stroke in individuals with diabetes compared to individuals with normoglycemia.

The analysis included 129 studies, with over ten million individuals from multiple countries. Ninety-seven studies with a median follow up of 9.8 years reported the primary outcome in the general population, and 32 studies with a median follow up of 3.2 years reported the primary outcome in patients with atherosclerotic cardiovascular disease. According to the Newcastle-Ottawa quality assessment scale, all studies were graded as good quality, except for 15 that were graded as fair quality.

In the general population, pre-diabetes was associated with an increased risk of all-cause death (RR 1.13, 95% CI 1.10-1.17), composite CVD (RR 1.15, 95% CI 1.11- 1.18), coronary heart disease (RR1.16, 95% CI 1.11- 1.21), and stroke (RR1.14, 95% CI 1.08-1.20).

In patients with atherosclerotic CVD, pre-diabetes was associated with all cause-death (RR 1.36, 95% CI 1.21-1.54), composite CVD (RR1.37,95% CI 1.23-1.53), and coronary heart disease (RR1.15, 95% CI 1.02-1.29), but no difference was seen for the risk of stroke (RR1.05, 95% CI 0.81-1.36).

A subgroup analysis was conducted according to sex, age, ethnicity, length of follow up, sample size, and quality of the study. The only significant finding was that in patients who were pre-diabetic with atherosclerotic CVD, the risk of all-cause mortality was higher in Asian patients (P=0.001 heterogeneity), and the risk of composite cardiovascular disease was higher in women with pre-diabetes than in men (P=0.002 heterogeneity).

It should be noted that one of the findings of the meta-analysis was that in the general population, impaired glucose tolerance was associated with a higher risk of complications than impaired fasting glucose, and the risk of all-cause mortality was mainly attributed to FPG of 110-125 mg/dL.

Practice Pearls:

• Severe complications, including increased risk of death, are tied to pre-diabetes.
• Multiple studies have shown an association between pre-diabetes and all-cause mortality and cardiovascular disease, both in the general population and in patients with atherosclerotic disease.
• Given the high prevalence of pre-diabetes, screening and rapid interventions are necessary to reduce mortality and prevent cardiovascular events in this population.

Dorte Vistisen, Mika Kivimäki, Leigh Perreault, et al. Reversion from pre-diabetes to normoglycaemia and risk of cardiovascular disease and mortality: the Whitehall II cohort study. Diabetologia. 2019 Aug;62(8):1385-1390.

Xiaoyan Cai, Yunlong Zhang, Meijun Li, et al. Association between pre-diabetes and risk of all-cause mortality and cardiovascular disease: an updated meta-analysis. BMJ. 2020 July 15;370:m2297.

Fairuz Afram, PharmD Candidate, University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences

See more about pre-diabetes in our condition center.