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Diabetes and metabolic syndrome

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factors for T2DM. OSA may adversely aect the course of T2DM complications such as retinopathy, kidney disease or foot ulcers. A recent longitudinal study reported worse cardiovascular prognoses in patients with T2DM and incident OSA compared to patients who did not develop OSA during follow-up.

Possible pathophysiological mechanisms that may explain the increased risk of metabolic syndrome and T2DM in OSA, independently of obesity, include intermittent hypoxia, oxidative stress, cytokine secretion and systemic inﬂammation (ﬁgure 1).

Oxidative stress can induce disturbances in glucose homeostasis, insulin resistance and dyslipidaemia. Intermittent hypoxia and sleep fragmentation provoke inﬂammatory cytokine secretion and provide a possible mechanism for development of metabolic syndrome in this setting via impaired insulin action in peripheral tissues and increased insulin resistance, dyslipidaemia and hypertension. OSA and metabolic syndrome are thus synergistic CVD risk factors. In the European Sleep Apnea Database (ESADA) cohort, a linear relationship between levels of total cholesterol, low-density lipoprotein, triglycerides and low levels of HDL and the severity of OSA (reﬂected by AHI or oxygen desaturation index) was observed. In particular, lipid levels were higher in OSA patients with central obesity.

There is a growing body of evidence that OSA is associated with nonalcoholic fatty liver disease (NAFLD), especially in obese patients. Insulin resistance, T2DM, obesity and intermittent hypoxia are contributors to liver dysfunction in OSA, from steatosis (nonalcoholic steatohepatitis (NASH)) to liver cirrhosis and hepatocarcinoma. A very high prevalence of NAFLD (64–91%), much higher than in the general population (∼25–30%), has been documented in OSA patients. The association between NAFLD and OSA persists in the absence of obesity. Furthermore, NAFLD severity increases with OSA severity.

Glycaemic control in diabetic patients, assessed as glycosylated haemoglobin level (HbA1c), is adversely aected by OSA. In the ESADA cohort, increasing AHI in patients with T2DM was associated with a linear increase in HbA1c. Poor glycaemic control correlated with the frequency of respiratory events occurring in REM sleep, but not in non-REM sleep, suggesting a role of OSA-associated sympathetic activation in its pathogenesis. Recent studies using continuous glucose monitoring have reported worse diurnal and nocturnal glucose proﬁles in diabetic patients with moderate-tosevere OSA compared to patients with mild OSA.

Treatment

Lifestyle modiﬁcations, including exercise and dietary changes (e.g. Mediterranean diet) are recommended to achieve weight loss and increased insulin sensitivity, with the goal of preventing the progression of the components of metabolic syndrome. In obese patients, weight loss of 5–10% leads to a decrease in BP, a better lipid proﬁle, improved insulin sensitivity and a reduction of inﬂammatory markers, ameliorating the risk of coronary heart disease. Orlistat can be added to lifestyle modiﬁcations to obtain weight loss. In the XENDOS (Xenical in the Prevention of Diabetes in Obese Subjects) randomised controlled trial (RCT), which included 3305 obese patients, orlistat treatment resulted in a weight loss of 2.4% aer 4 years, and was also eective for decreasing the risk of T2DM, lowering BP and improving insulin sensitivity and lipid proﬁles, as orlistat acts by decreasing the absorption of intestinal fat.

The impact of CPAP treatment on glucose metabolism remains unclear. A metaanalysis including 443 participants with metabolic syndrome (duration of CPAP intervention >2 weeks) showed a signiﬁcant improvement in insulin resistance,

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measured by the Homeostatic Model Assessment index, but fasting glucose levels remained unchanged. Similar observations have been reported for lipid metabolism: it is still unclear whether CPAP treatment can improve dyslipidaemia and reduce cardiovascular risk in patients with OSA.

In patients with T2DM and OSA, a recent meta-analysis of RCTs showed that CPAP treatment decreased HbA1c, fasting glucose, insulin resistance and SBP and DBP, but previous similar meta-analyses were negative. Such dierent results may derive from dierences in sample size, or from the poor sensitivity of HbA1c measurements to day–night changes compared to continuous glucose monitoring measurements over 24 h, which have shown improved glycaemic proﬁles during CPAP treatment. CPAP use for 4 h per night may be insucient to aect glycaemic control, whereas studies assessing the eects of CPAP treatment for 8 h per night showed signiﬁcant metabolic improvement and decreased sympathetic activity in patients with prediabetes or T2DM aer just 1 or 2 weeks of treatment.

Another study focused on patients with obesity and moderate-to-severe OSA who were randomly assigned to CPAP treatment, weight-loss, or CPAP plus weight-loss intervention for 24 weeks. Triglyceride levels were signiﬁcantly reduced in the weightloss and combined-intervention groups, but not in the CPAP-alone group. Therefore, CPAP alone does not appear to be sucient to improve metabolic changes in obese OSA patients.

In the ESADA cohort, the long-term eects of CPAP therapy on lipid proﬁle were analysed. Aer adjustment for age, sex, lipid-lowering medication, change in weight, CPAP compliance and duration, only total cholesterol levels decreased signiﬁcantly during follow-up, and duration of CPAP therapy was the only independent predictor for cholesterol reduction.

As for other metabolic disturbances in OSA, the eect of CPAP on NAFLD is controversial. In the majority of recent studies, no impact of CPAP alone was observed.

Isolating the role of CPAP on dysmetabolic aspects of OSA remains challenging, as many confounders can inﬂuence metabolic syndrome: CPAP adherence, CPAP duration, glycaemic control, the use and duration of antidiabetic and lipid-lowering drugs, sedentarity, obesity, physical activity and diet.

New drugs

Several drugs are currently used to delay the occurrence of T2DM, with interesting recent developments. Metformin is associated with reduction of body weight, waist circumference, fasting plasma glucose and triglycerides, and has been shown to provide a 31% risk reduction of developing T2DM at 3 years.

Glucagon-like peptide (GLP)-1 receptor agonists are a recently developed antidiabetic drug class, including albiglutide, liraglutide, lixisenatide, exenatide, semaglutide and dulaglutide, administered subcutaneously or orally. These drugs mimic the eects of incretin in the body, and seem to be safe and well tolerated. In a recent review that included 56 004 patients, a cardiovascular mortality reduction of 12% in T2DM was achieved. As well as improving glycaemic control, weight loss, BP and total cholesterol reduction were also observed. More recently, interesting data have been published on the cardiovascular impact of liraglutide in metabolic syndrome. Although the exact mechanism of action is still unknown, it seems that this molecule achieves direct anti-atherosclerotic action by decreasing plaque formation and progression. Similar to metformin, liraglutide treatment is associated with body weight and waist

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Diabetes and metabolic syndrome

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circumference reductions in metabolic syndrome. Moreover, liraglutide, semaglutide and dulaglutide are eective for reducing fat liver content and for achieving resolution of NASH in up to 42% of patients. The ROMANCE RCT on the eects of liraglutide alone or combined with CPAP in diabetic OSA patients is ongoing.

Sodium/glucose cotransporter (SGLT)-2 inhibitors (gliﬂozins) are novel therapeutic agents for T2DM that inhibit glucose reabsorption in renal proximal tubules. These drugs also improve glycaemic control and reduce body weight and BP, achieving the goal of decreasing cardiovascular events in metabolic syndrome. SGLT-2 inhibitors appear to exert protective eects toward cardiovascular and respiratory diseases, including OSA. A recent study showed that the combination of metformin and dapagliﬂozin led to resolution of metabolic syndrome in 77% of patients and was more eective than monotherapies. Another RCT found that empagliﬂozin reduced cardiovascular events in both OSA and non-OSA diabetic patients, and reduced the incidence of OSA during follow-up, possibly in association with body weight reduction. Other smaller studies have reported similar eects, but it is still unclear whether SGLT-2 inhibitors may exert additional protective eects in OSA patients.

Conclusion

Metabolic syndrome, T2DM and OSA are closely linked. OSA exerts a negative inﬂuence on metabolic functions through several physiopathological mechanisms related to intermittent hypoxia, respiratory eorts, sleep fragmentation and sympathetic activity. Although the role of CPAP in the metabolic dysfunction associated with OSA is not well established, a recent meta-analysis showed a positive eect of CPAP for decreasing HbA1c, fasting glucose, insulin resistance and SBP and DBP. Beyond weight loss and metformin, new drugs such as GLP-1 receptor agonists and gliﬂozins have shown signiﬁcant improvements in glycaemic control and reduction of body weight and BP. These treatments can resolve NASH in a signiﬁcant proportion of patients and appear to also exert protective eects towards the occurrence of cardiovascular and respiratory diseases, including OSA, in T2DM patients.

Further reading

• Adderley NJ, et al. (2020). Obstructive sleep apnea, a risk factor for cardiovascular and

microvascular disease in patients with type 2 diabetes: ﬁndings from a population-based cohort study. Diabetes Care; 43: 1868–1877.

• Anothaisintawee T, et al. (2016). Sleep disturbances compared to traditional risk factors for

diabetes development: systematic review and meta-analysis. Sleep Med Rev; 30: 11–24.

• Aurora RN, et al. (2022). Glucose proﬁles in obstructive sleep apnea and type 2 diabetes

mellitus. Sleep Med; 95: 105–111.

• Bonsignore MR (2022). Metabolic consequences of obstructive sleep apnea. In: Janes SM, ed.

Encyclopedia of Respiratory Medicine. 2nd Edn. Cambridge, Academic Press; pp. 50–59.

• Framnes SN, et al. (2018). The bidirectional relationship between obstructive sleep apnea and

metabolic disease. Front Endocrinol; 9: 440.

• Grimaldi D, et al. (2014). Association of obstructive sleep apnea in rapid eye movement sleep

with reduced glycemic control in type 2 diabetes: therapeutic implications. Diabetes Care; 37: 355–363.

• Gündüz C, et al. (2018). Obstructive sleep apnoea independently predicts lipid levels: data

from the European Sleep Apnea Database. Respirology; 23: 1180–1189.

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• Kent BD, et al. (2014). Diabetes mellitus prevalence and control in sleep-disordered breathing:

the European Sleep Apnea Cohort (ESADA) study. Chest; 146: 982–990.

• Neeland IJ, et al. (2020). The impact of empagliﬂozin on obstructive sleep apnea and

cardiovascular and renal outcomes: an exploratory analysis of the EMPA-REG OUTCOME trial. Diabetes Care; 43: 3007–3015.

• Shang W, et al. (2021). Beneﬁts of continuous positive airway pressure on glycaemic control

and insulin resistance in patients with type 2 diabetes and obstructive sleep apnoea: a metaanalysis. Diabetes Obes Metab; 23: 540–548.

• Umbro I, et al. (2020). Association between non-alcoholic fatty liver disease and obstructive

sleep apnea. World J Gastroenterol; 26: 2669–2681.

• Xu S, et al. (2015). The association between obstructive sleep apnea and metabolic syndrome:

a systematic review and meta-analysis. BMC Pulm Med; 15: 105.

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Hypothyroidism and

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acromegaly

Marie Bruyneel and Sonia Deweerdt

The relationships between endocrine and metabolic disorders and OSA are complex and bidirectional (ﬁgure 1). A high frequency of OSA has been observed in several endocrine disorders, including obesity, acromegaly, hypothyroidism, and diabetes mellitus. Improvements of OSA symptoms can be observed upon treatment of the underlying endocrine disorder.

Hypothyroidism

The thyroid gland produces two main hormones, T3 (triiodothyronine) and T4 (thyroxine), that regulate numerous physiological processes in the body. These processes include body temperature maintenance, digestion, and vital functions such as heart rate and respiration. Abnormal overgrowth of the thyroid (goitre) can lead to mechanical compression of surrounding structures. These goitres can be observed in euthyroid individuals, or in case of hypothyroidism and hyperthyroidism.

Hypothyroidism refers to the common pathological condition of thyroid hormone deﬁciency. Dierent degrees of severity of hypothyroidism can be observed, from subclinical hypothyroidism (SCH) to overt hypothyroidism (OH), associated with dierent clinical and biological characteristics (table 1).

Chronic autoimmune thyroiditis, also called Hashimoto disease, is the most common cause of hypothyroidism and is associated with high levels of anti-thyroid antibodies, typically anti-thyroid peroxidase and anti-thyroglobulin antibodies. Iodine deﬁciency,

Key points

• The most important mechanisms responsible for OSA in overt hypothyroidism (OH) are disturbance of the regulatory control of pharyngeal dilator muscles due to neuropathy, severe myxoedema, macroglossia and goitre.

• Treatment of OH can ameliorate OSA severity but is probably insucient to cure OSA.

• OSA in acromegaly patients results from facial skeletal deformities, pharyngeal and tongue thickening, and tissue oedema.

• Treatment of acromegaly can improve the severity of OSA or even cure it, but only in 60% of cases.

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Hypothyroidism and acromegaly

Acromegaly

OSA

Diabetes

mellitus type 1

Diabetes

mellitus type 2

Cushing

syndrome

Obesity

Figure 1. Illustration of the bidirectional relationships between endocrine disorders and OSA. Solid arrows indicate a strong relationship, while discontinuous arrows indicate a weak relationship.

which is common in Europe, can also result in goitre, thyroid nodules, and hypothyroidism. Salt iodisation remains the recommended strategy for eliminating iodine deﬁciency.

Hypothyroidism is associated with an increased prevalence of OSA. Until recently, the prevalence of OSA in patients with OH or SCH had not been well established. A recent systematic review estimated the prevalence of OSA in OH patients to be 25–50%. In

Table 1. Clinical and biological characteristics of overt and subclinical hypothyroidism

Biology

Risk factors Women

Prevalence

General population 1–10% 1–2% Obese individuals 14% 15% OSA patients 25–50% Unknown

Clinical manifestations Macroglossia

OH SCH

↑ TSH ↑ TSH

↓ T4

Obesity in older people (age >65 years)

Caucasian individuals

Puy face

Cold intolerance

Fatigue

Dry skin

Constipation

Weight gain

Bradycardia

Diastolic dysfunction

Insulin resistance

Dyslipidaemia

Diastolic hypertension

Normal T4

Atherosclerosis

Insulin resistance

Dyslipidaemia

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a cross-sectional study, comparing prevalence of OSA in 514 OH patients and 4917 controls, multivariate logistic regression analysis showed an OR for OSA of 1.88 (95% CI 1.24–2.84).

The level of thyroid dysfunction does not appear to predict OSA severity. A number of dierent mechanisms, mainly related to respiratory physiology, have been suggested to explain the association between OH and OSA. The most important of these mechanisms relates to the neuropathic disturbance of regulatory control of dilator muscles of the pharynx and possible depression of the respiratory centre. Upper airway (UA) obstruction can also be caused by severe myxoedema, macroglossia and mucoprotein deposition in the UA. Despite the fact that SCH is associated with a higher prevalence of risk factors (e.g. atherosclerosis, hyperlipidaemia and insulin resistance) compared with OH, it has no severe impacts on respiratory physiology and the link between SCH and OSA is not comparable to that of OH.

Goitre, alone or associated with OH, can be the source of OSA. UA obstruction responsible for OSA because of mechanical compression by the goitre causes UA oedema associated with decreased venous return from the head and neck.

The goal of OH and SCH treatment is to normalise thyroid-stimulating hormone (TSH) and T4 levels. Thyroid hormone replacement therapy generally achieves normalisation of thyroid function and improves BMI, skinfold thickness, blood glucose and serum lipids. It may also ameliorate OSA in OH. However, OSA resolution (obtained in 66% of patients treated with hormone replacement therapy) was reported in only a few older studies, which observed signiﬁcant reductions in apnoea periods, oxygen desaturation index, snoring and choking in limited samples of patients. Because other factors, for example age, obesity, male sex and menopausal status in women, can also contribute to OSA, it is unlikely that hormone replacement therapy alone will be sucient for resolving OSA in OH patients.

In clinical practice, thyroid disorders, which are observed in 8.2% of newly diagnosed OSA patients, should be excluded; especially in symptomatic or atrisk patients, as treatment of OH (and potentially of SCH) can help improve OSA. The Zulewski score, a clinical tool based on 14 symptoms and signs, could help clinicians to detect OH.

Acromegaly

Acromegaly is a rare but serious medical condition resulting from persistent hypersecretion of growth hormone (GH) from the pituitary gland. In most of the cases, hypersecretion originates from a somatotroph adenoma of the pituitary gland. GH stimulates hepatic production of insulin-like growth factor-1 (IGF-1), leading to the clinical manifestations of the disorder. Clinical manifestations include acral and so tissue overgrowth, joint pain, diabetes mellitus, hypertension, and heart and respiratory failure. Acromegaly is a disabling disease that is associated with increased morbidity and reduced life expectancy.

In patients with OSA, the prevalence of acromegaly has recently been shown to be much higher than that of the general population at 0.14–0.17%, aecting 30–70 individuals per million. There is a female predominance in the disorder.

OSA is found in 69% of patients with active acromegaly. Several mechanisms are responsible for OSA development. Acromegaly induces facial skeletal deformities, related to overgrowth of mandible and maxilla bones (ﬁgure 2). Pharyngeal and tongue thickening, associated with glycosaminoglycan deposition and increased

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Figure 2. Typical acromegaly facial features in two patients suering from acromegaly. Enlarged mandible and maxilla bones and so tissue overgrowth are observed.

collagen production by aected connective tissue, can result in UA narrowing. In addition, direct stimulation of sodium channels in the epithelium by GH and IGF-1 causes increased sodium reabsorption in the kidney leading to tissue oedema that further contributes to OSA. Another factor that contributes to OSA in patients with acromegaly is that they are oen overweight.

In acromegaly, CSA is less common than OSA and is typically observed in patients with higher GH and IGF-1 levels who have an increased ventilatory response to carbon dioxide.

Figure 3. Comparison of a normal hand (on the le) with an acromegaly patient’s hand (right), showing acral enlargement and so tissue overgrowth.

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Acromegaly treatment aims to lower IGF-1 and GH levels to normal ranges. Treatment is based on transsphenoidal resection of the adenoma, together with a long-acting somatostatin analogue if necessary. Radiotherapy can be proposed in case of treatment failure.

Studies have shown that transsphenoidal surgery and long-acting somatostatin analogue treatment was associated with a signiﬁcant improvement in OSA severity in 60% of the cases of cured or controlled acromegaly. Indeed, UA narrowing, pharyngeal so tissue swelling and macroglossia, due to excess GH, may be partially reversible aer treatment but not in all patients. Up to 40% of acromegaly–OSA patients exhibit persistent OSA, despite good disease control. Excess weight or associated OH can contribute to the persistence of OSA. Therefore, OSA should be closely monitored (clinically and by PSG/polygraphy (PG)) aer acromegaly treatment initiation.

Screening for acromegaly is not yet recommended in OSA. However, since 50% of acromegaly patients present with facial and acral enlargement (macroglossia, large hands (ﬁgure 3) and feet) at diagnosis, clinicains should pay attention to these typical clinical signs in newly diagnosed OSA patients. The ACROSCORE, a 14-point scoring tool based on signs, symptoms and comorbidities, can be used to help clinicians detect acromegaly patients. Early acromegaly diagnosis avoids long-term consequences due to lack of treatment of this disease.