Editor's Note: Commentary based on Liu A, Cardell J, Ariel D. Abnormalities of Lipoprotein Concentrations in Obstructive Sleep Apnea Are Related to Insulin Resistance. Sleep 2015; 38(5):793-9. doi: 10.5665/sleep.4678.

Background

There is a high prevalence of atherosclerotic cardiovascular disease (ASCVD) in patients with obstructive sleep apnea (OSA). Dyslipidemia notably triglyceride and cholesterol elevation with lower high density lipoprotein (HDL) have been reported in patients with OSA. Insulin resistance is a known risk factor for hypertriglyceridemia and low HDL levels and is independently associated with OSA and ASCVD. The relationship of dyslipidemia in OSA patients with insulin resistance was evaluated in this study.

Methods

In this cross-sectional study at academic medical center conducted over 40 months, nondiabetic, overweight to obese (BMI 26-38 kg/m²) adult volunteers were invited to participate. Exclusion criteria included history of Type 2 Diabetes, known ASCVD, hepatic or renal insufficiency, use of medications that may affect glucose or lipid metabolism or weight loss agents and previous treatment for OSA. Fasting plasma lipid/lipoprotein analysis was performed by vertical auto profile (VAP) methodology measuring all five major classes of lipoproteins: low density lipoprotein (LDL), very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), high density lipoprotein (HDL), lipoprotein A (Lp. A). OSA severity was rated using the apnea-hypopnea index (AHI) measured with polysomnography. Hypoxia measures included minimum oxygen saturation (min O2), mean oxygen saturation (mean O2) and oxygen desaturation index (ODI). Insulin resistance was quantified by measuring steady state plasma glucose concentration (SSPG) during the modified octreotide insulin suppression test.

Results

One hundred and seven adult volunteer who met eligibility criteria consented to participate. This cohort included 64% men, and 65% study participants were Caucasian. The notable demographics include mean age was 50 years, mean BMI was 30.6 kg/m², mean fasting plasma glucose was 101 mg/dl, mean SSPG was 170 mg/dl (range from 51 to 309 mg/dl). 24 % had mild OSA, 31 % had moderate OSA, and 45% had severe OSA. 27.1% of participants were on lipid-lowering therapy. There was a strong association between lipoprotein concentrations and SSPG, which was preserved after adjusting for age, sex and BMI. SSPG was positively correlated with TG (r=0.30, p< 0.01), total VLDL and its subclasses VLDL₁₊₂ (r=0.21-0.23, p< 0.05), LDL₄ (r=0.30, p< 0.01), apo B/apo A1 ratio (r= 0.29, p< 0.01) and negatively correlated with HDL (r= -0.38, p< 0.001) and its subclasses (HDL₂, HDL₃), (r= -032, r= -0.43, p<0.01), LDL₂ (r= -0.30, p< 0.01), apo A1(r= -0.33, p< 0.01) and Lp A (r= -0.28, p< 0.01). There was no correlation between total LDL or LDL-Real and SSPG. FPG was positively correlated with TG, LDL₃, LDL₄, VLDL₁₊₂, apo B and apo B/apoA1 ratio. There was no significant correlation between lipoprotein concentrations and AHI or hypoxia measures after adjusting for age, sex, BMI. There was also no association between SSPG and AHI. There was an increase in concentrations of TG, LDL₄, VLDL, VLDL₁₊₂ and apo B/apoA1 ratio and decrease in concentrations of HDL and its subclasses (HDL₂, HDL₃), LDL₂, apo A1 and Lp A across SSPG tertiles. These associations remained statistically significant after adjusting for age, sex and BMI. By contrast, there was no significant trend between OSA severity and lipoprotein measurements. The densest LDL B pattern was predominant in insulin resistant group (64%) and LDL pattern A was more frequent in insulin-sensitive group (80%). There was no association between LDL pattern and OSA severity.

Conclusion

In summary, lipoprotein abnormalities in patients with OSA are closely associated with insulin resistance, but not with OSA severity or degree of hypoxia. This study highlights the role of insulin resistance in OSA-related dyslipidemia and increased cardiovascular disease risk in these subjects.

Commentary/Perspective

Metabolic abnormalities and high prevalence of ASCVD have been described in patients with OSA.^1,2 It is questionable whether lipoprotein abnormalities noted in patients with OSA arise from insulin resistance, or from underlying sleep apnea. In this cross-sectional study authors highlight the strong correlation between insulin resistance and dyslipidemia in patients with OSA. Similar results have been shown in healthy adults.³

This study suggests the lack of association between OSA severity and lipoprotein abnormalities or insulin resistance. It is well known that African-American men at age younger than 39 and at age 50-59 demonstrate high severity of OSA vs White men at the same age after controlling the BMI.⁴ There is a high proportion of Caucasian subjects in this study population which have skewed outcomes, although there was a fair spread of patients across the OSA spectrum.

Another noteworthy feature is the severity of dyslipidemia. It has been shown that men with OSA have higher total and LDL cholesterol compared with age and BMI matched subjects without OSA.⁵ Higher degree of dyslipidemia appears to be reported in patients with OSA.⁶

This study brings to attention the possible role of insulin resistance in accelerating dyslipidemia in OSA patients who are at an increased risk of ASCVD. Given the high prevalence of ASCVD in OSA subjects, annual screening for insulin resistance may prove to be useful.

References

1. Coughlin SR, Mawdsley L, Mugarza JA, Calverley PM, Wilding JP. Obstructive sleep apnea is independently associated with an increased prevalence of metabolic syndrome. Eur Heart J 2004; 25:735–41. [PubMed]
2. Dong JY, Zhang YH, Qin LQ. Obstructive sleep apnea and cardiovascular risk: meta-analysis of prospective cohort studies. Atherosclerosis 2013; 229:489–95.
3. Chu JW, Abbasi F, Kulkarni KR, et al. Multiple lipoprotein abnormalities associated with insulin resistance in healthy volunteers are identified by the vertical auto profile-II methodology. Clin Chem 2003; 49:1014–7.
4. Pranathiageswaran S; Badr MS; Severson R; Rowley JA. The influence of race on the severity of sleep disordered breathing. J Clin Sleep Med 2013;9(4):303-309.
5. Nigel McArdle, David Hillman, Lawrie Beilin, and Gerald Watts. Metabolic Risk Factors for Vascular Disease in Obstructive Sleep Apnea. Am J Resp Crit Care Med 2007; 175 (2): 190-195
6. Nadeem R, Singh M, Nida M, Waheed I, Khan A, Ahmed S, Naseem J, Champeau D. Effect of obstructive sleep apnea hypopnea syndrome on lipid profile: a meta-regression analysis. J Clin Sleep Med 2014; 10(5):475-489.

Keywords: Anti-Obesity Agents, Apnea, Sleep Apnea Syndromes, Sleep Apnea, Obstructive, Apolipoprotein A-I, Apolipoproteins B, Body Mass Index, Cardiovascular Diseases, Cholesterol, Cholesterol, LDL, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Dyslipidemias, Fasting, Glucose, Hypertriglyceridemia, Insulin, Insulin Resistance, Lipid Metabolism, Lipoprotein(a), Lipoproteins, HDL, Lipoproteins, IDL, Lipoproteins, VLDL, Obesity, Octreotide, Overweight, Oxygen, Polysomnography, Prevalence, Renal Insufficiency, Risk Factors, Triglycerides

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