Lower Is Better for Blood Glucose to Reduce Heart Disease

Marlene Busko

August 18, 2023

Men and women with prediabetes, undiagnosed diabetes, and, notably, diagnosed diabetes were at higher risk of incident cardiovascular disease (CVD), whereas those with low-normal A1c were at lower risk of this in a large, 12-year observational study of UK Biobank data.

The results highlight "the need for strategies to reduce risk of CVD across the [glycemic] spectrum," urge Christopher T. Rentsch, MPH, PhD, and colleagues in their study, which was published August 11 in the The Lancet Regional Health  Europe.

The findings suggest "that excess [CVD] risks in both men and women were largely explained by modifiable factors and could be ameliorated by attention to weight reduction strategies and greater use of antihypertensive and statin medications.

"Addressing these risk factors could reduce sex disparities in [glycemia]-related risks of CVD," according to the researchers.

After accounting for age, the absolute rate of CVD events was higher among men than women (16.9 vs 9.1 events per 1000 person-years); however, the relative risk was higher among women than men.

Compared to men, women were more likely to have obesity (63% vs 53%) and were less likely to be using antihypertensive medications (64% vs 69%) or a statin (71% vs 75%).

"This is the largest study to date to investigate sex differences in the risk of CVD across the glycemic spectrum," say the researchers.

"The Lower the Better"

"We uncovered compelling evidence that for blood sugar levels within the 'normal' range, it was a case of 'the lower the better' in protecting against heart disease," Rentsch, assistant professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, United Kingdom, told Medscape in an email.

Compared to people with normal blood glucose levels, those with lower than normal levels were at 10% lower risk of developing any form of heart disease, he noted.

The study findings "support women being proactive in asking about medications like statins and antihypertensives as an option to help lower their [CVD] risk, if clinically appropriate," Rentsch added.

"We found that men and women with diagnosed diabetes remained at elevated risk for three types of heart disease — coronary artery disease, stroke, and heart failure — even after accounting for a large number of sociodemographic, lifestyle, and clinical characteristics," he pointed out.

However, "total cholesterol, family history of CVD, estimated glomerular filtration rate, and C-reactive protein had relatively little impact on explaining the risk of heart disease associated with blood sugar."

"It is well established that being overweight can lead to higher blood sugar levels as well as higher blood pressure, these being factors that contribute to higher risk of heart attack and stroke," Robert Storey, DM, professor of cardiology, University of Sheffield, United Kingdom, told the UK Science Media Centre.

"This very large UK Biobank study," he said, "shows that the higher heart risk associated with blood sugar can be detected at a very early stage along the path towards the abnormally high blood sugar levels associated with diabetes.

"The study provides support for a strategy of assessing cardiovascular risk in people who are overweight, including assessment of blood sugar, cholesterol, and blood pressure levels, all of which can be effectively managed to markedly reduce the risk of future heart attack and stroke," according to Storey.

More Than 400,000 Men, Women

The researchers enrolled men and women aged 40-69 between 2006 to 2010 who were living in England, Scotland, and Wales. After excluding people with type 1 diabetes or those whose A1c data were missing, the current study included 427,435 people (46% men).

The participants were classified as having low-normal A1c (<35 mmol/mol or <5.5%), normal A1c (35–41 mmol/mol or 5.5% to 5.9%), prediabetes (42–47 mmol/mol or 6.0% to 6.4%), undiagnosed diabetes (≥48 mmol/mol or ≥6.5%), or diagnosed type 2 diabetes (medical history and in receipt of glucose-lowering medication).

The researchers determined the incidence of six CVD outcomes during a median 11.8-year follow-up: coronary artery disease, atrial fibrillation, deep vein thrombosis, pulmonary embolism, stroke, and heart failure.

Few participants (5%) had any of these outcomes prior to study enrollment.

During the follow-up, there were 51,288 incident CVD events.

After adjusting for age, compared with having normal A1c, having prediabetes or undiagnosed diabetes was associated with an increased risk of CVD for women and men (hazard ratio [HR], 1.30 – 1.47).

Among individuals with diagnosed type 2 diabetes, the age-adjusted risk of CVD was greater for women (HR, 2.00) than for men (HR, 1.55).

After further adjustment for clinical and lifestyle factors, especially obesity and antihypertensive or statin use, the risk of CVD decreased and became similar among men and women. The fully adjusted HR for CVD was 1.17 for women and 1.06 for men with diagnosed diabetes.

Compared to having normal A1c, women and men with low-normal A1c were at decreased risk of CVD (HR, 0.86 for both).

The study was funded by Diabetes UK and the British Heart Foundation. Rentsch and Storey have disclosed no relevant financial relationships. The disclosures of the other study authors are listed in the original article.

Lancet Reg Health Eur. Published online August 9, 2023. Full text

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