Paradoxical Effects of Prolonged Insufficient Sleep on Lipid Profile: A Pooled Analysis of 2 Randomized Trials

Abstract

Background Insufficient sleep is associated with increased cardiovascular disease risk, but causality is unclear. We investigated the impact of prolonged mild sleep restriction (SR) on lipid and inflammatory profiles. Methods and Results Seventy-eight participants (56 women [12 postmenopausal]; age, 34.3±12.5 years; body mass index, 25.8±3.5 kg/m²) with habitual sleep duration 7 to 9 h/night (adequate sleep [AS]) underwent two 6-week conditions in a randomized crossover design: AS versus SR (AS-1.5 h/night). Total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, triglycerides, and inflammatory markers (CRP [C-reactive protein], interleukin 6, and tumor necrosis factor-α) were assessed. Linear models tested effects of SR on outcomes in the full sample and by sex+menopausal status (premenopausal versus postmenopausal women+men). In the full sample, SR increased high-density lipoprotein cholesterol compared with AS (β=1.2±0.5 mg/dL; P=0.03). Sex+menopausal status influenced the effects of SR on change in total cholesterol (P-interaction=0.04), LDL-C (P-interaction=0.03), and interleukin 6 (P-interaction=0.07). Total cholesterol and LDL-C decreased in SR versus AS in premenopausal women (total cholesterol: β=-4.2±1.9 mg/dL; P=0.03; LDL-C: β=-6.3±2.0 mg/dL; P=0.002). Given paradoxical effects of SR on cholesterol concentrations, we explored associations between changes in inflammation and end point lipids under each condition. Increases in interleukin 6 and tumor necrosis factor-α during SR tended to relate to lower LDL-C in premenopausal women (interleukin 6: β=-5.3±2.6 mg/dL; P=0.051; tumor necrosis factor-α: β=-32.8±14.2 mg/dL; P=0.027). Conclusions Among healthy adults, prolonged insufficient sleep does not increase atherogenic lipids. However, increased inflammation in SR tends to predict lower LDL-C in premenopausal women, resembling the "lipid paradox" in which low cholesterol associates with increased cardiovascular disease risk in proinflammatory conditions. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02835261, NCT02960776.

Keywords: clinical trial; inflammation; insufficient sleep; lipid profile; sleep.

Figure 1. The CONSORT flow diagram for this randomized crossover study with 2 sleep conditions. CONSORT indicates Consolidated Standards for Reporting of Trials.

Figure 2. Mean±SEM levels of circulating TC (A), LDL‐C (B), HDL‐C (C), and TG (D) across weeks under conditions of AS and mild SR in the full sample.

Across women of both menopausal statuses and men, HDL‐C was increased in SR relative to AS (P=0.03). Sex+menopausal status influenced the relationship between sleep condition and change in TC (P‐interaction=0.04; E) and LDL‐C (P‐interaction=0.03; F). Stratified analyses showed that TC (E) and LDL‐C (F) decreased in SR relative to AS among premenopausal women (Pre; TC: P=0.03; LDL‐C: P=0.002) but not postmenopausal women+men (Post+Men; both P>0.20). AS indicates adequate sleep; HDL‐C, high‐density lipoprotein cholesterol; LDL‐C, low‐density lipoprotein cholesterol; SR, sleep restriction; TC, total cholesterol; and TG, triglycerides.

Figure 3. Mean±SEM levels of circulating proinflammatory cytokines CRP (A), TNF‐α (B), and IL‐6 (C) across weeks under conditions of AS and mild SR in the full sample.

Sleep condition did not significantly affect any markers of inflammation in the full sample. There was a trend toward a significant influence of sex+menopausal on the relationship between sleep condition and IL‐6, which increased in SR relative to AS in premenopausal women (Pre) compared with postmenopausal women+men (Post+Men) (P‐interaction=0.069; D). AS indicates adequate sleep; CRP, C‐reactive protein; IL‐6, interleukin 6; SR, sleep restriction; and TNF‐α, tumor necrosis factor‐α.