In general, patients with an office systolic blood pressure (SBP) ≥ 140 mm Hg and a diastolic blood pressure (DBP) ≥ 90 mmHg are deemed to have hypertension (HT). The overall prevalence of HT in adults is reportedly around 30–45% [1]. Obstructive sleep apnea (OSA) is a condition with recurrent apnea and hypopnea, frequent arousal, and hypoxemia, which can lead to serious cardiovascular consequences such as HT, heart failure, arrhythmia, and atherosclerosis [2]. As an important cause of morbidity and mortality, HT accounted for the deaths of approximately 10 million people in 2015 and over 200 million disability-adjusted life years [3]. Blood pressure normally drops during sleep. A nocturnal decrease of more than 10% in the mean blood pressure level throughout the day is defined as the “dipping pattern”. The absence of this decrease indicates a nondipping pattern. One of the important causes for the nondipping pattern is OSA ^[4][5][4,5]. Here, the sympathetic nervous system is activated due to the obstructed airway in patients with OSA, resulting in the disruption of the natural dipping pattern and causing an increase in blood pressure [5]. Traditionally recognized risk factors for cardiovascular diseases (CVDs), such as obesity, insulin resistance, diabetes mellitus, and hyperlipidemia, are common in OSA patients, and the most common CVD in patients with OSA is HT. The coexistence of OSA and chronic obstructive pulmonary disease (COPD) is called overlap syndrome [6], and individuals with overlap syndrome have a significantly increased risk of HT compared with those with COPD alone [7].

2. Epidemiology of OSA and Hypertension

HT and OSA often coexist. Pensukan et al. found a significant relationship between OSA and elevated blood pressure (odds ratio (OR): 2.38; 95% confidence interval (CI): 1.68–3.39), and HT (OR: 2.55; 95% CI: 1.57–4.15) after adjusting for demographic characteristics ^[8][9]. OSA has been reported among 30–50% of hypertensive patients. This rate can increase to 80% among cases with drug-resistant HT ^[9][10][11][10,11,12]. It has also been reported that masked HT is 2.7 times more common in OSA patients ^[12][13][13,14]. There is a bidirectional and causal relationship between HT and OSA. Several studies have revealed a clear dose–response relationship with OSA severity and HT. The meta-analyses on the relationship between OSA and HT are summarized in Table 1 ^{[14][15][16][17]}[15,16,17,18]. The Sleep Heart Health Study (SHHS), a large-scale, community-based, multicenter, cross-sectional study conducted with 6152 participants, reported an increased OR of 1.37 (95% CI: 1.03–1.83) of HT in those with severe OSA after adjusting for confounding factors ^[11][12]. Different results have been reported on the relationship between OSA and HT in prospective studies. One of these studies was the Wisconsin Sleep Cohort Study, which was conducted with 709 participants. The results indicated a dose–response relationship independent of known confounding factors between sleep-disordered breathing and new-onset HT 4 years later ^[18][19]. Similarly, in the Zaragoza Sleep Cohort Study, a prospective, observational study conducted with 1889 participants for a mean follow-up duration of 12.2 years, an increased risk of new-onset HT was detected in untreated OSA patients after adjusting for confounding factors, including apnea hypopnea index (AHI), age, sex, baseline SBP, DBP, and body mass index (BMI) ^[19][20]. In contrast, in the Victoria sleep cohort study conducted with 1557 participants for a follow-up duration of 7.5 years, no relationship was found between OSA and the incidence of HT ^[20][21]. Along these lines, the 5-year follow-up study of the SHHS, conducted with 2470 participants without HT at admission, found that after adjusting for BMI, AHI was no longer a significant predictor of HT. The findings that do not support the relationship between OSA and HT were attributed to the lower rate of participants with moderate-to-severe OSA. Indeed, the vast majority (around 87%) of the participants included in the 5-year follow-up of the SHHS had mild OSA, defined as an AHI between 5 and 15 events/h ^[21][22]. A meta-analysis of seven studies by Xia W et al., published in 2018, including 6 prospective cohort studies and 1 case-control study, conducted with a total of 6098 participants, reported that high AHI values were related to a significantly increased risk of essential HT compared with low AHI values (OR 1.77, 95% CI 1.30–2.41, p = 0.001). The results of the linear dose–response meta-analysis indicated that the risk of essential HT increased by 17% for every 10 events/hour increase in the AHI (OR 1.17, 95% CI 1.07–1.27, p = 0.001). Moreover, the nonlinear dose–response found in the meta-analysis results revealed that the risk of essential HT increased with AHI ^[22][23]. Similarly, a recent meta-analysis by Yuan F. et al. published in 2021, including 8 studies conducted with a total of 3484 OSA patients, revealed a significant association between OSA and HT (OR 6.44, 95% CI 5.38–7.71, p < 0.001) and between OSA severity and HT ^[16][17].

3. Pathogenesis of Hypertension in OSA

The mechanisms promoting HT in OSA are multifactorial. Sympathetic activity due to intermittent hypoxia is one of the mechanisms triggering the elevation in blood pressure in OSA. Sympathetic activity due to the hypoxemic state causes both vasoconstriction and the stimulation of chemoreceptors. Consequently, the renin–angiotensin–aldosterone system (RAAS) is activated, the endothelin-1 level is increased, and the nitric oxide level is decreased, all of which contribute to the increase in vascular resistance and the development of HT ^[23][24][24,25]. In addition, RAAS activation increases the amount of angiotensin-2, a strong vasoconstrictor, in the blood and, thus, blood pressure ^[25][26]. Increased aldosterone levels also contribute to the development of HT by causing fluid and sodium retention ^[26][27]. Sympathetic hyperactivity leads to a proinflammatory state, resulting in endothelial injury and oxidative stress ^[27][28][28,29]. The other factors that play a role in the pathogenesis of HT in OSA are obesity, gut dysbiosis, rostral fluid shifts, pharyngeal collapse, nocturnal energy expenditure, and metabolic derangements ^[23][24] (Figure 1).

4. Clinical Characteristics of Hypertension in OSA

In patients with OSA, HT is predominantly nocturnal and characterized by a high DBP, masked HT, and a nondipping pattern [4]. Blood pressure is normally the highest during the mid-morning, gradually decreasing as the day progresses, down to 10% of the wakefulness value during sleep, and reaches its lowest value at 3 a.m. This dipping pattern is correlated with the duration of deep sleep. It has been reported that the expected decrease in blood pressure may not occur in the case of several diseases such as OSA. Important cardiovascular consequences may occur in patients who have such diseases who are referred to as “nondippers” ^[29][30][30,31]. Nocturnal blood pressure elevation is correlated with the severity of OSA ^[31][32]. The nondipping blood pressure pattern was reported at a rate of 84% in OSA patients who did not receive treatment ^[32][33]. Nocturnal and nondipping HT is closely associated with target organ damage and the development of cardiovascular diseases ^[33][34]. Additionally, it has been reported that night-time blood pressure variability, which is related to increased target organ damage, was higher in a OSA group than in a non-OSA group ^[34][35][35,36]. The pathogenesis of the nondipping pattern and blood pressure variability is multifactorial. Intermittent hypoxia and recurring microarousals are major events leading to sleep fragmentation, reduced slow-wave sleep, and increased sympathetic activity, resulting in elevated blood pressure and increased blood pressure variability ^[36][37].

5. Treatment Modalities

Among the treatment modalities that come to the fore in the treatment of OSA in patients with HT are CPAP, diuretics, renal denervation, use of maxillomandibular advancement devices, and hypoglossal nerve stimulation surgery for restricted airways or tonsillar enlargement. Weight loss, physical exercise, reducing alcohol consumption, and smoking cessation are among the primary lifestyle changes recommended for hypertensive patients with OSA ^[37][38].

6. Pharmacological Therapies of HT in Patients with OSA

6.1. Antihypertensive Medications

Current guidelines for HT do not make specific recommendations on the pharmacological treatment modalities for patients with concomitant OSA and HT. Given the increased sympathetic activity and renin–angiotensin–aldosterone (RAAS) activity in OSA patients, medications that block these pathways are highlights. Among the antihypertensive medications that were initially preferred were angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) ^[38][39]. It was also demonstrated that beta-blockers mitigate night-time blood pressure rise and apnea-related tachycardias ^[39][40]. An earlier study conducted by Hedner et al. compared the effects of atenolol, hydrochlorothiazide, amlodipine, enalapril, and losartan on office and ambulatory blood pressures in 40 individuals with HT and OSA ^[40][41]. Each participant received two of the aforementioned five agents (balanced incomplete block design) for 6 weeks, with a 3-week washout period in-between. Compared with the other four drugs, atenolol lowered the office diastolic BP as well as mean night-time ambulatory SBP and DBP ^[40][41]. These findings support the hypothesis that overactivity of the sympathetic nervous system is the most important mechanism involved in the development of HT in adults with OSA ^[40][41].

6.2. Diuretics

Two small studies have suggested that the use of spironolactone, an aldosterone antagonist, may efficiently decrease blood pressure in OSA patients with treatment-resistant HT ^[41][42][42,43]. Similarly, eplerenone, another aldosterone antagonist, was shown to significantly decrease blood pressure in hypertensive OSA patients ^[43][44]. Recent studies have shown that primary aldosteronism is common in patients with moderate-to-severe OSA, a finding that indicates aldosterone antagonists may be beneficial in this patient group ^[44][45][46][45,46,47]. There are also studies suggesting that aldosterone antagonists may reduce the frequency of apnea by mitigating laryngeal edema in OSA patients ^[41][45][42,46]. Taken together, these findings suggest that aldosterone antagonist diuretics, especially spironolactone, may be effective in the treatment of HT in OSA patients. However, large-scale cohort studies are needed to elucidate the efficacy of aldosterone antagonist diuretics in treating HT in OSA patients.

6.3. Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors

Canagliflozin, one of the SGLT2 inhibitors that has recently been the focus in the treatment of cardiac failure, was shown to provide significant nocturnal blood pressure reductions in adults with diabetes, treatment-resistant HT, and OSA ^[47][48].

7. CPAP Therapy for OSA in Patients with HT

A number of studies have shown that CPAP therapy results in a modest reduction of 2–3 mmHg in SBP and of 1.5–2 mmHg in DBP in OSA patients (Table 2) ^{[48][49][50][51][52][53][54][55]}[49,50,51,52,53,54,55,56]. On the other hand, this reduction is higher in adults with treatment-resistant HT. Although a 1–2 mmHg decrease in blood pressure may not be considered much, even such a slight decrease in blood pressure was shown to be associated with significant decrease sin cardiovascular mortality and stroke risk ^[56][57].