Novel Lipid Indicator Identifies Risk of Ischemic Heart Disease in T2D

A new investigation identified a link between an elevated non-high-density lipoprotein cholesterol (non-HDL-C) to high-density lipoprotein cholesterol (HDL-C) ratio (NHHR) and the likelihood of ischemic heart disease (IHD) among patients with type 2 diabetes (T2D).1

Across a median follow-up of nearly 13 years, this large, prospective cohort study, involving nearly 20,000 patients in the UK Biobank, documented 3600 cases of IHD, with most participants reported in the highest NHHR quartile.

“Our study provides evidence supporting the potential clinical utility of the NHHR in assessing IHD risk among patients with T2D,” wrote the investigative team, led by Sikun Zhang, department of cardiology, Second Xiangya Hospital of Central South University. “The NHHR may facilitate early risk identification and targeted management.”

With a significantly higher prevalence among people with T2D, compared with the general population, IHD is a cardiovascular complication defined by cardiac coronary ischemia and myocardial injury. Dyslipidemia plays a notable role in the progression of IHD—lipid markers, including low-density lipoprotein cholesterol (LDL-C) and HDL-C, do not often capture the complexity of the condition for this population.

Citing the need for a novel lipid index to boost risk assessment, Zhang and colleagues indicated the NHHR could integrate atherogenic and anti-atherogenic lipoprotein effects, enhancing predictive accuracy for CV outcomes in T2D.2 Primary analysis of the UK Biobank, a large-sample prospective study with nearly 500,000 participants between 2006 and 2010, targeted 19,925 eligible participants with T2D.3

Participants had a self-reported history of diabetes, self-reported medication use for diabetes, hospital inpatient records of T2D, and glycated hemoglobin A1c (HbA1c) levels ≥48 mmol/mol. Investigators calculated the NHHR using HDL-C and total cholesterol levels in the UK Biobank.1

Four groups were created, based on the quartiles of the NHHR. Subgroup analyses evaluated the link between the NHHR and the incident risk of IHD, stratified by demographic factors, including age, sex, ethnicity, education level, income, body mass index (BMI), smoking status, and alcohol drinking status.

The study population had a median age of 61 and comprised 51.8% males. Those in the highest NHHR quartile were more likely to be White, smoke currently, and have a higher BMI, waist circumference, blood glucose, HbA1c, and triglycerides, compared with the lowest quartile.

Further analysis showed the highest NHHR quartile revealed a significantly greater risk of IHD compared with the other quartiles (P <.0001). After adjusting for ethnicity, education, income, lifestyle factors, and diabetes duration, the association for the highest quartile remained robust (hazard ratio [HR], 1.42; 95% CI, 1.18–1.71; P <.001), while the association in Quartile 3 lost significance (HR, 1.04; 95% CI, 0.86–1.26; P = .672).

In the fully adjusted model, each unit increase in NHHR was linked to a 12% increase in IHD risk (HR, 1.12; 95% CI, 1.04–1.22; P =.003). Zhang and colleagues observed no significant nonlinear relationship between the NHHR index and incident IHD risk in the fully adjusted RCS analysis (P for nonlinearity =.9490; P for overall <.0001).

Results were similar across four sensitivity analyses. Subgroup analysis revealed a significant interaction between the NHHR indicator and drinking status (P =.038), suggesting drinking had a joint effect with NHHR on IHD incidence in people with T2D. Compared with current drinkers, IHD risk was more prominent in those who were never or previous drinkers (HR, 1.16; 95% CI, 1.06–1.26; P =.001).

Zhang and colleagues noted these data benefit the understanding of the link between lipid metabolism and IHD, supporting the management of lipid metabolic parameters to prevent IHD in people with T2D.

“This novel lipid biomarker not only outperformed conventional lipid parameters in evaluating atherosclerosis but also showed superior accuracy in predicting diabetes-related conditions,” Zhang and colleagues wrote. “Given its remarkably predictive efficacy, cost-effectiveness, and ease of calculation, the NHHR holds promising prospects for clinical applications.”

References

1. Zhang S, Zhu Z. The association between non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) and the risk of ischemic heart disease in type 2 diabetes mellitus participants: a large-scale cohort study from the UK Biobank. Diabetol Metab Syndr. 2025;17(1):99. Published 2025 Mar 24. doi:10.1186/s13098-025-01646-3

2. Lazarte J, Hegele RA. Dyslipidemia Management in Adults With Diabetes. Can J Diabetes. 2020;44(1):53-60. doi:10.1016/j.jcjd.2019.07.003

3. Hodkinson A, Tsimpida D, Kontopantelis E, Rutter MK, Mamas MA, Panagioti M. Comparative effectiveness of statins on non-high density lipoprotein cholesterol in people with diabetes and at risk of cardiovascular disease: systematic review and network meta-analysis. BMJ. 2022;376:e067731. Published 2022 Mar 24. doi:10.1136/bmj-2021-067731