Sleep Apnea and Cardiovascular Risk in Patients with Prediabetes and Type 2 Diabetes

Obstructive sleep apnea (OSA) is a common but largely undiagnosed clinical condition, which is turning into a serious public health issue. Of note is that its prevalence is gradually increasing in parallel with the obesity and type 2 diabetes mellitus (T2DM) epidemics. The aim of this article is to comprehensively review the literature in order to evaluate the cardiovascular (CV) risk among patients with OSA and prediabetes or T2DM. OSA seems to be an independent risk factor for the development as well as the progression of T2DM, whereas it is associated with T2DM-related macrovascular and microvascular complications. OSA may also act as a potential risk factor for the presentation and development of CV disease, such as hypertension, coronary artery disease, heart failure, pulmonary hypertension, atrial fibrillation and other cardiac arrythmias, as well as stroke. OSA and T2DM also share common pathophysiological mechanisms leading to atherosclerosis. Considering that the coexistence of OSA and T2DM is an independent and cumulative risk factor for CV mortality, more so than the two diseases separately, clinicians and healthcare professionals should be aware of and screen for OSA in patients with T2DM. Notably, targeted therapy for both conditions seems to substantially improve CV prognosis.


OSA: Prevalence, Diagnosis, Pathophysiology, and Treatment
Obstructive sleep apnea (OSA) is a common but largely undiagnosed clinical condition, which is turning into a serious public health issue. It affects almost 1 billion people worldwide, and more than 30 million people are underdiagnosed in Europe [1,2]. Of note is that its prevalence is gradually increasing in parallel with the obesity and diabetes epidemics [3]. OSA is characterized by autonomous nervous system disturbances and the recurrent complete or partial collapse of upper airways (apneas or hyponeas) during sleep, leading to intrathoracic pressure changes, periodic reduction, or cessations in airflow; as a result, hypoxia, hypercapnia and frequent arousals from sleep occur [3,4].
 OSA was associated with 2. 5  OSA was associated with a 2-fold increased risk in MACEs and cerebrovascular events in patients with T2DM following successful PCI.
Patients with OSA and T2DM were at higher risk of CAD by 55%, AF by 53%, HF by 67%, as well as stroke or TIA by 57%, PN by 32%, DFD by 42%, CKD by 18% and albuminuria by 11%, and all-cause mortality by 24%.
Strausz et al. [ likely to develop CAD and HF when compared to those diagnosed only with T2DM [104]. Interestingly, risk of CVD and mortality rates are even more elevated if T2DM is diagnosed before OSA [105]. Therefore, patients with T2DM who develop OSA are a high-risk population for CVD, and clinicians should be aware of this bidirectional association and the CV complications, which are about to be further discussed. The main studies evaluating the CV risk among patients with OSA and prediabetes or T2DM are presented in Table  1. Evidence reveals that both T2DM and OSA are independent risk factors for the development and the progression of CVD. Indeed, patients with OSA and T2DM are more likely to develop CAD and HF when compared to those diagnosed only with T2DM [104]. Interestingly, risk of CVD and mortality rates are even more elevated if T2DM is diagnosed before OSA [105]. Therefore, patients with T2DM who develop OSA are a high-risk population for CVD, and clinicians should be aware of this bidirectional association and the CV complications, which are about to be further discussed. The main studies evaluating the CV risk among patients with OSA and prediabetes or T2DM are presented in Table  1.  OSA was associated with a 2-fold increased risk in MACEs and cerebrovascular events in patients with T2DM following successful PCI.
follow-up: 5 years likely to develop CAD and HF when compared to those diagnosed only with T2DM [104]. Interestingly, risk of CVD and mortality rates are even more elevated if T2DM is diagnosed before OSA [105]. Therefore, patients with T2DM who develop OSA are a high-risk population for CVD, and clinicians should be aware of this bidirectional association and the CV complications, which are about to be further discussed. The main studies evaluating the CV risk among patients with OSA and prediabetes or T2DM are presented in Table  1.  OSA was associated with a 2-fold increased risk in MACEs and cerebrovascular events in patients with T2DM following successful PCI.
OSA in combination with T2DM at baseline was associated with a 3,4-fold higher prevalence of CVD as well as a 2,3-fold increase in cardiovascular mortality.
Wang et al. [110] BMJ Open Diabetes Res Care Prospective cohort study ing the CV risk among patients with OSA and prediabetes or T2DM are presented in Table   1. the CV complications, which are about to be further discussed. The main studies evaluat-ing the CV risk among patients with OSA and prediabetes or T2DM are presented in Table   1. population for CVD, and clinicians should be aware of this bidirectional association and the CV complications, which are about to be further discussed. The main studies evaluat-ing the CV risk among patients with OSA and prediabetes or T2DM are presented in Table   1.  population for CVD, and clinicians should be aware of this bidirectional association and the CV complications, which are about to be further discussed. The main studies evaluat-ing the CV risk among patients with OSA and prediabetes or T2DM are presented in Table   1.

CVD Risk among Patients with Sleep Apnea and Prediabetes or T2DM
Evidence reveals that both T2DM and OSA are independent risk factors for the development and the progression of CVD. Indeed, patients with OSA and T2DM are more likely to develop CAD and HF when compared to those diagnosed only with T2DM [104]. Interestingly, risk of CVD and mortality rates are even more elevated if T2DM is diagnosed before OSA [105]. Therefore, patients with T2DM who develop OSA are a high-risk population for CVD, and clinicians should be aware of this bidirectional association and the CV complications, which are about to be further discussed. The main studies evaluating the CV risk among patients with OSA and prediabetes or T2DM are presented in Table  1.

CVD Risk among Patients with Sleep Apnea and Prediabetes or T2DM
Evidence reveals that both T2DM and OSA are independent risk factors for the development and the progression of CVD. Indeed, patients with OSA and T2DM are more likely to develop CAD and HF when compared to those diagnosed only with T2DM [104]. Interestingly, risk of CVD and mortality rates are even more elevated if T2DM is diagnosed before OSA [105]. Therefore, patients with T2DM who develop OSA are a high-risk population for CVD, and clinicians should be aware of this bidirectional association and the CV complications, which are about to be further discussed. The main studies evaluating the CV risk among patients with OSA and prediabetes or T2DM are presented in Table  1.

CVD Risk among Patients with Sleep Apnea and Prediabetes or T2DM
Evidence reveals that both T2DM and OSA are independent risk factors for the development and the progression of CVD. Indeed, patients with OSA and T2DM are more likely to develop CAD and HF when compared to those diagnosed only with T2DM [104]. Interestingly, risk of CVD and mortality rates are even more elevated if T2DM is diagnosed before OSA [105]. Therefore, patients with T2DM who develop OSA are a high-risk population for CVD, and clinicians should be aware of this bidirectional association and the CV complications, which are about to be further discussed. The main studies evaluating the CV risk among patients with OSA and prediabetes or T2DM are presented in Table  1.

CVD Risk among Patients with Sleep Apnea and Prediabetes or T2DM
Evidence reveals that both T2DM and OSA are independent risk factors for the development and the progression of CVD. Indeed, patients with OSA and T2DM are more likely to develop CAD and HF when compared to those diagnosed only with T2DM [104]. Interestingly, risk of CVD and mortality rates are even more elevated if T2DM is diagnosed before OSA [105]. Therefore, patients with T2DM who develop OSA are a high-risk population for CVD, and clinicians should be aware of this bidirectional association and the CV complications, which are about to be further discussed. The main studies evaluating the CV risk among patients with OSA and prediabetes or T2DM are presented in Table  1. OSA was associated with a 2-fold increased risk in MACEs and cerebrovascular events in patients with T2DM following successful PCI.
Wang et al. [112] Diabetes Ther Systematic review and meta-analysis

CVD Risk among Patients with Sleep Apnea and Prediabetes or T2DM
Evidence reveals that both T2DM and OSA are independent risk factors for the de-velopment and the progression of CVD. Indeed, patients with OSA and T2DM are more likely to develop CAD and HF when compared to those diagnosed only with T2DM [104].
Interestingly, risk of CVD and mortality rates are even more elevated if T2DM is diag-nosed before OSA [105]. Therefore, patients with T2DM who develop OSA are a high-risk population for CVD, and clinicians should be aware of this bidirectional association and the CV complications, which are about to be further discussed. The main studies evaluat-ing the CV risk among patients with OSA and prediabetes or T2DM are presented in Table   1.

CVD Risk among Patients with Sleep Apnea and Prediabetes or T2DM
Evidence reveals that both T2DM and OSA are independent risk factors for the de-velopment and the progression of CVD. Indeed, patients with OSA and T2DM are more likely to develop CAD and HF when compared to those diagnosed only with T2DM [104].
Interestingly, risk of CVD and mortality rates are even more elevated if T2DM is diag-nosed before OSA [105]. Therefore, patients with T2DM who develop OSA are a high-risk population for CVD, and clinicians should be aware of this bidirectional association and the CV complications, which are about to be further discussed. The main studies evaluat-ing the CV risk among patients with OSA and prediabetes or T2DM are presented in Table   1.

CVD Risk among Patients with Sleep Apnea and Prediabetes or T2DM
Evidence reveals that both T2DM and OSA are independent risk factors for the de-velopment and the progression of CVD. Indeed, patients with OSA and T2DM are more likely to develop CAD and HF when compared to those diagnosed only with T2DM [104].
Interestingly, risk of CVD and mortality rates are even more elevated if T2DM is diag-nosed before OSA [105]. Therefore, patients with T2DM who develop OSA are a high-risk population for CVD, and clinicians should be aware of this bidirectional association and the CV complications, which are about to be further discussed. The main studies evaluat-ing the CV risk among patients with OSA and prediabetes or T2DM are presented in Table   1.

CVD Risk among Patients with Sleep Apnea and Prediabetes or T2DM
Evidence reveals that both T2DM and OSA are independent risk factors for the development and the progression of CVD. Indeed, patients with OSA and T2DM are more likely to develop CAD and HF when compared to those diagnosed only with T2DM [104]. Interestingly, risk of CVD and mortality rates are even more elevated if T2DM is diagnosed before OSA [105]. Therefore, patients with T2DM who develop OSA are a high-risk population for CVD, and clinicians should be aware of this bidirectional association and the CV complications, which are about to be further discussed. The main studies evaluating the CV risk among patients with OSA and prediabetes or T2DM are presented in Table  1.

CVD Risk among Patients with Sleep Apnea and Prediabetes or T2DM
Evidence reveals that both T2DM and OSA are independent risk factors for the development and the progression of CVD. Indeed, patients with OSA and T2DM are more likely to develop CAD and HF when compared to those diagnosed only with T2DM [104]. Interestingly, risk of CVD and mortality rates are even more elevated if T2DM is diagnosed before OSA [105]. Therefore, patients with T2DM who develop OSA are a high-risk population for CVD, and clinicians should be aware of this bidirectional association and the CV complications, which are about to be further discussed. The main studies evaluating the CV risk among patients with OSA and prediabetes or T2DM are presented in Table  1.

CVD Risk among Patients with Sleep Apnea and Prediabetes or T2DM
Evidence reveals that both T2DM and OSA are independent risk factors for the development and the progression of CVD. Indeed, patients with OSA and T2DM are more likely to develop CAD and HF when compared to those diagnosed only with T2DM [104]. Interestingly, risk of CVD and mortality rates are even more elevated if T2DM is diagnosed before OSA [105]. Therefore, patients with T2DM who develop OSA are a high-risk population for CVD, and clinicians should be aware of this bidirectional association and the CV complications, which are about to be further discussed. The main studies evaluating the CV risk among patients with OSA and prediabetes or T2DM are presented in Table  1.

CVD Risk among Patients with Sleep Apnea and Prediabetes or T2DM
Evidence reveals that both T2DM and OSA are independent risk factors for the development and the progression of CVD. Indeed, patients with OSA and T2DM are more likely to develop CAD and HF when compared to those diagnosed only with T2DM [104]. Interestingly, risk of CVD and mortality rates are even more elevated if T2DM is diagnosed before OSA [105]. Therefore, patients with T2DM who develop OSA are a high-risk population for CVD, and clinicians should be aware of this bidirectional association and the CV complications, which are about to be further discussed. The main studies evaluating the CV risk among patients with OSA and prediabetes or T2DM are presented in Table  1. Interestingly, OSA among patients with T2DM significantly increases the risk of developing CVD, as well as the respective rates of mortality. According to a population-Nutrients 2022, 14, 4989 7 of 14 based cohort study of 3667 patients and 10,450 matched controls, patients who developed OSA after their diagnosis of T2DM were at higher risk of developing ischemic CAD by 55%, HF by 67%, and stroke or transient ischemic attack (TIA) by 57%, when compared to patients with T2DM and no OSA [106]. As a result, all-cause mortality was detrimentally increased by 24%. In the secondary analysis exploring outcomes in participants with T2DM and prevalent OSA compared with T2DM only, patients with OSA continued to be at increased risk of composite CVD [106].
There is evidence that both the presence and severity of OSA seem to increase the risk of cardiac arrhythmias among patients with T2DM. Patients with T2DM who developed OSA are at higher risk of developing AF by 53% compared with patients without diagnosed OSA [106]. Additionally, a recent cross-sectional study revealed that the presence and severity of OSA are strongly correlated with a 2.3-fold increased risk of QTc prolongation among patients with T2DM [97]. Of note, among patients with T2DM and QTc ≥ 418 ms, older patients (OR: 1.042, 95% CI: 1.042-1.064, p < 0.001), females (OR: 2.36, 95% CI: 1.371-4.063, p < 0.01), and patients with higher BMI (OR: 1.113, 95% CI: 1.037-1.195, p < 0.01) were significantly more likely to have OSA. These data provide evidence that OSA-related QTc prolongation may be an additional risk factor for CVD in patients with T2DM, highlighting the importance of evaluating global CV screening for arrhythmia risk stratification [113].
According to the current literature, OSA seems to be an independent risk factor not only for T2DM, but also for T2DM-related macrovascular and microvascular complications. According to a population-based cohort study of 3667 patients and 10,450 matched controls, patients with T2DM who developed OSA are at higher risk of developing peripheral neuropathy by 32%, diabetic foot disease by 42%, chronic kidney disease by 18%, and albuminuria by 11% when compared to patients with T2DM and no OSA [106]. In a longitudinal, large-scale population-based cohort study in Finland, including 36,963 participants, it was indicated that patients with OSA face a 36% greater risk of CVD, after a follow-up of 25 years, than the general population [107]. Notably, this risk was even prominent among women, who usually remain undiagnosed and untreated. Furthermore, patients with OSA had a 1,75-fold increased risk of diabetic kidney disease [107]. In particular, patients with both T2DM and OSA had an even higher risk of CVD (by 36%) and diabetic kidney disease, and, therefore, a markedly increased all-cause mortality when compared to those with T2DM and no OSA [107].
Moreover, T2DM seems to increase the risk of MACEs by 64%, as well as hospitalization for unstable angina and all-end events among patients with OSA [108]. In this cohort study, patients with OSA and T2DM experienced more end-events after a median follow-up of 42 months when compared to patients without T2DM. Interestingly, overweight and obese females ≥ 70 years with T2DM and mild OSA present a substantially higher risk of MACEs. Furthermore, the SantOSA cohort, a prospective cohort study of 1447 patients, verifies that the coexistence of OSA and T2DM is a greater independent risk factor for CV mortality than either of the two diseases in isolation. Moreover, OSA in combination with T2DM at baseline was associated with a 3,4-fold higher prevalence of CVD, as well as a 2,3-fold increased CV mortality after a median follow-up of 5 years [109].
Similarly, OSA is associated with a 2.5-fold increased risk of 1-year MACEs among patients with T2DM following ACS, but not in patients without T2DM [110]. Combined OSA and longer hypoxia duration, defined as time with arterial oxygen saturation < 90% for more than 22 min, leads to a further risk in the MACEs by 31.0% in patients with T2DM. Moreover, there is evidence that the presence of OSA among patients with T2DM postpercutaneous coronary intervention (PCI) leads to adverse outcomes, worsening patients' prognoses. Moreover, it has been reported that OSA is associated with a 2-fold risk in MACEs and cerebrovascular events in patients with T2DM after 3 years of successful PCI, but not in those with no T2DM [111]. Indeed, ACS leading to adverse CV outcomes is mainly provoked by new lesions of thin cap fibroatheromas in non-culprit vessels among patients with T2DM [114]. Similarly, severe and untreated OSA is strongly correlated with high rates of repeated revascularizations after PCI, mainly to non-target lesions [115]. The increased risk of MACEs and all-cause mortality among OSA patients with T2DM is also verified by Wang et al. According to a recent meta-analysis of 1168 patients with T2DM following PCI (of whom 614 had co-existing OSA), MACEs and all-cause mortality were significantly higher in the OSA subgroup [112]. Therefore, patients with T2DM and coexisting OSA face a greater risk for adverse CV outcomes after PCI when compared to those with T2DM and no OSA, thus requiring close monitoring and strict management strategies. Notably, the increased risk of CV events is predominately reported in patients with OSA and poor glycemic control at baseline [112]. Therefore, the co-existence of OSA and T2DM seems to have a synergistic effect, thus promoting the development and progression of atherosclerosis, as well as increasing the risk of CV events among these patients.
These results provide evidence that OSA and T2DM share common mechanisms of atherosclerosis, leading to serious CV events, as presented in Figure 1. OSA-induced repeated hypoxemia accompanied by reoxygenation has been associated with low-grade chronic systemic inflammation, oxidative stress, and endothelial dysfunction, thus triggering the development of T2DM and the related macrovascular and microvascular complications. Specifically, the inflammatory profile of OSA is characterized by the recruitment of macrophages and the presence of circulating inflammatory biomarkers, such as C-Reactive Protein (CRP), chemokines and cytokines such as Interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), nuclear factor kappa B (NFK-B), as well as adhesions molecules such as selectins, intracellular adhesion molecule-1 (ICAM-1), and vascular intracellular adhesion molecule-1 (VCAM-1) [116,117]. Furthermore, OSA may disrupt the balance between pro-oxidant and antioxidant factors. High levels of superoxide anions in circulating leukocytes, production of ROS, increase in lipid peroxidation, and decrease in antioxidant defense have been reported among patients with OSA, possibly due to the repetition of hypoxia-reoxygenation cycles [118,119]. Hypoxia inducible factor-1 (HIF-1), a major transcription factor, is activated by hypoxia, and when chronic, it negatively modifies the transcription of plenty genes, thus provoking detrimental consequences for CV system [120].  According to the current literature, CPAP seems to be a quite beneficial therapy for the management of OSA. Nevertheless, among patients with established CVD and OSA, CPAP therapy does not improve glycemic control among patients with prediabetes or T2DM over standard care treatment. Moreover, CPAP therapy did not modify serum glucose levels, hemoglobin A1C (hbA1c) or antidiabetic medication among these patients after a median follow up of 4.3 years [121]. Similarly, empagliflozin, a sodium glucosecotransporter inhibitor −2 (SGLT-2i), seems to be quite promising [122][123][124]. In the EMPA- According to the current literature, CPAP seems to be a quite beneficial therapy for the management of OSA. Nevertheless, among patients with established CVD and OSA, CPAP therapy does not improve glycemic control among patients with prediabetes or Nutrients 2022, 14, 4989 9 of 14 T2DM over standard care treatment. Moreover, CPAP therapy did not modify serum glucose levels, hemoglobin A1C (hbA1c) or antidiabetic medication among these patients after a median follow up of 4.3 years [121]. Similarly, empagliflozin, a sodium glucose -cotransporter inhibitor −2 (SGLT-2i), seems to be quite promising [122][123][124]. In the EMPA-REG OUTCOME trial, 6% of the participants had OSA at baseline, and these patients faced higher rates of CV and renal events, as well as higher comorbidity during the trial [125]. Notably, empagliflozin improved cardiometabolic risk factors, as well as MACEs, hospitalization for HF, mortality, and renal outcomes, regardless of pre-existing OSA. It may also decrease the incidence of new-onset OSA, possibly due to weight loss and the favorable effect of visceral adiposity [126]. Moreover, metformin, the cornerstone in the management of T2DM, may improve sleep quality, although it does not modify the prevalence of OSA, according to retrospective cohort studies [127,128]. Despite that, these preliminary data remain weak and should be further examined and elucidated.

Conclusions
Current evidence indicates that both T2DM and OSA are independent risk factors for the development and the progression of CVD. These chronic conditions seem to share detrimental pathophysiological pathways, increasing the risk of CV complications and markedly worsening patient prognosis. This effect is especially profound and synergistic when these two clinical conditions co-exist. Thus, patients with T2DM who develop OSA are at higher CV risk, and as a result clinicians and healthcare professionals should be aware of OSA co-existence among patients with T2DM. Of note, targeted therapy for OSA and T2DM seems to substantially improve their CV prognosis. Nevertheless, OSA still remains undiagnosed and untreated in everyday clinical practice. Thereby, personalized medicine approach, careful assessment of co-morbidities, as well as better CV risk stratification and CVD prevention among patients with T2DM and OSA are of major importance.