In a study of nearly half a million Chinese adults with no history of diabetes, higher random plasma glucose (RPG) levels, even within the normal range, were associated with higher risks for all major cardiovascular diseases (CVDs)[1].

After a mean follow-up of 7 years, UK investigators found positive, log-linear associations between usual or longer-term RPG levels and the risk for CV death and major ischemic CVD that continued through at least a usual RPG level of 5.9 mmol/L (106 mg/dL) and no evidence of a threshold.

The association was observed for ischemic stroke and major occlusive vascular disease in the normal range of glucose levels as low as 4.3 mmol/L (77 mg/dL). Increased risk for CV death, major coronary events, and intracerebral hemorrhage was seen at levels as low as 5.8 mmol/L (104 mg/dL), compared with the reference group (<4.3 mmol/L).

Each 1-mmol/L (18-mg/dL)–higher usual RPG level above 5.9 mmol/L was associated with an approximately 10% higher CVD risk after adjustment.

The findings “support consideration of blood glucose levels as a continuous variable (rather than simply the presence or absence of diabetes) in cardiovascular risk-prediction models and suggest the need to consider CVD primary prevention at glucose levels below the diabetes threshold,” Dr Fiona Bragg (University of Oxford, England) and colleagues write in their study, published online July 20, 2016 in JAMA Cardiology.

The study provides the first convincing evidence of a positive association of RPG levels with CVD, they say. Prospective studies, mainly in Western populations using fasting blood glucose levels, have shown a relatively consistent greater CVD risk in the prediabetes range, but evidence below this range is conflicting.

Bragg notes that fasting or postload blood glucose levels may be more robust than RPG levels, which can have larger interindividual and intraindividual variation, but that “nonfasting glucose levels may be more relevant to CVD risks because people spend most time in a nonfasting state.”
This speculation is “plausible and worth further investigation,” Dr Lijing Yan (Duke Kunshan University, China), Heng Jiang (Wuhan University, China), and Dr Carolyn SP Lam (National Heart Centre and Duke National University of Singapore) write in an accompanying editorial[2].

The relationship between RPG levels and CV outcomes “appeared to be significant, continuous, and linear,” but they note that “risks remained modest (5%–30%) until glucose levels reached 11.1 mmol/L (200 mg/dL), which is high enough to diagnose diabetes if 2-hour postload glucose levels were used.”

Further, adding glucose to the multivariable models only minimally improved the predictive power, “suggesting that no value would be added for including this variable in risk-prediction models.”

Prospective Data

Bragg and her team previously reported[3] a positive association of RPG levels with prevalent CVD in people aged 30 to 79 years recruited from 2004 to 2008 in the China Kadoorie Biobank (CKB), but the findings were limited by the use of cross-sectional data and self-reported disease outcomes.

The present study used prospective 7-year follow-up data from the CKB for 467,508 adults aged 30 to 79 years (59% women; mean age 50.9 years) without diabetes who were recruited over the same period and followed until January 2014. A nonfasting blood sample was collected from participants at all but one of the 10 study locations, and plasma glucose levels were measured using the SureStepPlus handheld glucose meter. The mean baseline RPG was 5.9 mmol/L (106 mg/dL).

he primary end points were determined through the China’s Disease Surveillance Points system, residential, health, and insurance records, and established disease registries. A particular strength of the study was validation by computed tomographic scan or MRI for more than 90% of stroke events, the editorialists observe.

After adjustment for covariables and regression dilution bias, each 1-mmol/L (18-mg/dL)–higher usual RPG level above 5.9 mmol (106 mg/dL) was associated with an 11% higher risk for CV death. The association appeared stronger in men than women (P=0.005) and in those with lower systolic BP (P for trend=0.002) or higher education levels (P=0.009).

The association with RPG level was weakest for intracerebral hemorrhage but was significant.

Adjusted Hazard Ratios for CVD by Usual RPG* Level

The investigators point out that the associations persisted after they excluded participants diagnosed with diabetes during follow-up, which “supports the existence of independent log-linear associations of RPG with CVD risks.”

They note that much more work is needed to establish the clinical utility of the data, but that from a public-health perspective even modest increases in risks translate into large health, social, and economic burdens.

“Therefore, results from this study, if confirmed, suggest the potential in measuring RPG levels—more practical to achieve than fasting or postload glucose levels—for screening, early detection, and prevention of diabetes and cardiovascular disease.”