Association between the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio and cardiovascular mortality among US adults with diabetes: a prospective cohort study of NHANES 1999–2018

Q: What are the key findings of this study?

Non-HDL to HDL cholesterol ratio was nonlinearly associated with cardiovascular mortality in diabetic adults, increasing risk per quartile.

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Diabetes mellitus (n=6581). Intervention: Non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) per one-quartile increase vs. Lowest NHHR quartile (Q1, <2.19). Primary outcome: Cardiovascular mortality (HR 1.11, 95% CI 1.00-1.22, p=0.043 for trend).

Q: What does this research mean for the field?

The non-HDL to HDL cholesterol ratio is nonlinearly associated with cardiovascular mortality in adults with diabetes, with the lowest risk observed at a ratio of approximately 2.5 to 3.0 and an increased risk per quartile increase above the nadir. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Rui Lin; Yangbo Chen; Youde Liu; Yongjian Lin; Zexiong Li; Shangbo Xu

doi:10.21203/rs.3.rs-10870769/v1

October 12, 2026Open Access

Association between the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio and cardiovascular mortality among US adults with diabetes: a prospective cohort study of NHANES 1999–2018

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Key result

Higher non-HDL/HDL ratio linked to ~11% higher cardiovascular mortality per quartile in diabetic adults.

HR 1.11
95% CI 1.00-1.22
P=0.043 for trend
n=6,581

Why the study?

The non-HDL-C to HDL-C ratio (NHHR) integrates information on atherogenic and anti-atherogenic lipoproteins, but its association with cardiovascular mortality in adults with diabetes remained unclear.

Is a higher non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) associated with increased cardiovascular mortality in US adults with diabetes?

Key Points

To evaluate the prospective association between the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) and cardiovascular mortality among US adults with diabetes.
Prospective cohort analysis of ten NHANES cycles (1999–2018) linked to mortality follow-up through December 31, 2019, including 6,581 adults with diabetes (N=6,581).
NHHR was calculated as (total cholesterol - HDL-C)/HDL-C and divided into survey-weighted quartiles: Q1 (<2.19), Q2 (2.19–3.03), Q3 (3.03–4.13), and Q4 (>4.13).
Survey-weighted cause-specific Cox models and restricted cubic splines evaluated cardiovascular mortality while adjusting for demographics, socioeconomic status, BMI, smoking, and hypertension.
Among 622 cardiovascular deaths, fully adjusted hazard ratios were 0.89 (95% CI, 0.67–1.19) for Q2, 1.07 (95% CI, 0.84–1.36) for Q3, and 1.31 (95% CI, 0.95–1.80) for Q4 compared with Q1.
The hazard ratio per one-quartile increase was 1.11 (95% CI, 1.00–1.22; P for trend=0.043), whereas the continuous increase per standard deviation was not statistically significant (HR, 1.08; 95% CI, 0.97–1.20; P=0.148).
Restricted cubic spline analysis showed a nonlinear association (P for overall association=0.024; P for nonlinearity=0.020), with the lowest estimated hazard at an NHHR of approximately 2.5–3.0.

Study Design

Type

Cohort (n=6,581)

Multicenter

Yes

Structured PICO

Is a higher non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) associated with increased cardiovascular mortality in US adults with diabetes?

P

Population

6,581 US adults aged ≥18 years with diabetes from ten NHANES cycles (1999–2018), linked to mortality follow-up through December 31, 2019.

E

Exposure

Non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR), calculated as (Total cholesterol - HDL-C) / HDL-C, analyzed by survey-weighted quartiles (Q2: 2.19–3.03, Q3: 3.03–4.13, Q4: >4.13) and continuously

C

Comparator

Lowest quartile of NHHR (Q1: <2.19) for categorical analyses, or median NHHR (2.95) for restricted cubic spline analysis

O

Outcome

Cardiovascular mortality (defined as deaths from diseases of the heart [UCOD_LEADING=1] or cerebrovascular diseases [UCOD_LEADING=5] via linkage to the National Death Index through December 31, 2019)hard clinical

Main Result

Hazard Ratio: 1.11 (95% CI 1–1.22)

p-value: p=0.043 for trend

In US adults with diabetes, the non-HDL-C to HDL-C ratio (NHHR) showed a modest nonlinear association with cardiovascular mortality (nadir ~2.5–3.0), though attenuation in sensitivity analyses precludes its current use as an independent prognostic marker.

Limitations

Observational design precludes causal inference and allows residual confounding by diet, physical activity, diabetes duration, comorbidities, and medication use.
Lipid measurements and covariates were assessed only at baseline, with no data on changes during follow-up.
Lipid-lowering medication use, particularly statin therapy, was not included in the primary model.
Complete-case analysis may have introduced selection bias.
Cardiovascular mortality was defined using the publicly available leading-cause recode rather than detailed individual-level ICD-10 codes.
Limited number of cardiovascular deaths led to imprecise estimates at the tails of the NHHR distribution.
Observational design precludes causal inference and is subject to residual confounding by diet, physical activity, diabetes duration, comorbidities, medication use, and socioeconomic factors
Lipid measurements and covariates were assessed only at baseline, with no data on changes during follow-up
Lipid-lowering medication use, particularly statin therapy, was not included in the primary model
Complete-case analysis may have introduced selection bias
Cardiovascular mortality was defined with the publicly available leading-cause recode rather than detailed individual-level underlying ICD-10 codes, and estimates at the tails of the NHHR distribution were imprecise due to a limited number of cardiovascular deaths

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Implication

Should not yet change practice in diabetes; hypothesis-generating for NHHR in CV risk stratification and needs prospective validation.

Abstract

Background: The non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) integrates information on atherogenic and anti-atherogenic lipoproteins. Its association with cardiovascular mortality in adults with diabetes remains unclear. Methods: We conducted a prospective cohort analysis of ten National Health and Nutrition Examination Survey (NHANES) cycles (1999-2018) linked to mortality follow-up through December 31, 2019. Diabetes was defined by self-reported diagnosis, insulin use, oral glucose-lowering medication use, or hemoglobin A1c (HbA1c) ≥6.5%. NHHR was calculated as (total cholesterol - HDL-C)/HDL-C. Survey-weighted cause-specific Cox models and restricted cubic splines were used to examine the association between NHHR and cardiovascular mortality. Results: The complete-case cohort comprised 6,581 adults with diabetes, including 622 cardiovascular deaths. Compared with Q1, the fully adjusted hazard ratios for cardiovascular mortality were 0.89 (95% confidence interval [CI], 0.67-1.19) for Q2, 1.07 (95% CI, 0.84-1.36) for Q3, and 1.31 (95% CI, 0.95-1.80) for Q4. The hazard ratio per one-quartile increase was 1.11 (95% CI, 1.00-1.22; P for trend=0.043). Restricted cubic spline analysis suggested a nonlinear association (P for overall association=0.024; P for nonlinearity=0.020), with the lowest estimated hazard at an NHHR of approximately 2.5-3.0. The direction of association was similar in sensitivity analyses, although statistical significance was attenuated. Conclusions: NHHR was nonlinearly associated with cardiovascular mortality among US adults with diabetes. Higher NHHR values above the apparent nadir were associated with a tendency toward higher cardiovascular mortality; however, the association was modest and less precise in sensitivity analyses. These findings warrant cautious interpretation and external confirmation.

Discussion

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Cite This Study

Lin et al. (2026) conducted a cohort in Diabetes mellitus (n=6,581). Non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) per one-quartile increase vs. Lowest NHHR quartile (Q1, <2.19) was evaluated on Cardiovascular mortality (HR 1.11, 95% CI 1.00-1.22, p=0.043 for trend). Non-HDL to HDL cholesterol ratio was nonlinearly associated with cardiovascular mortality in diabetic adults, increasing risk per quartile.

synapsesocial.com/papers/6aee6b6871a759480622091e https://doi.org/10.21203/rs.3.rs-10870769/v1

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Association between the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio and cardiovascular mortality among US adults with diabetes: a prospective cohort study of NHANES 1999–2018

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Association between the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio and cardiovascular mortality among US adults with diabetes: a prospective cohort study of NHANES 1999–2018

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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