Abstract
Previous reports indicated the therapeutic effect of chronic continuous positive airway pressure (CPAP) therapy on cardiac hypertrophy due to sleep apnea syndrome. However, little is known for cases involving diabetic complications. This retrospective observational study examined the effects of CPAP therapy on left ventricular hypertrophy (LVH) in patients with obstructive sleep apnea syndrome (OSAS) and type 2 diabetes mellitus (T2DM). For all cases, the observation period was 3 years from the time when the patient was introduced to CPAP therapy. Overall, 123 patients were divided into a good CPAP group (CPAP ≥4 h/day, n = 63) and non-adherence group (CPAP <4 h/day, n = 60). The mean CPAP usage times were 5.58 ± 1.23 and 1.03 ± 1.17 h/day in the good CPAP and non-adherence groups, respectively. Regression tendencies of the thickness of the left ventricular posterior (–0.30 ± 1.19 mm) and interventricular septal walls (–0.48 ± 1.22 mm) were observed in the good CPAP group. Hypertrophic tendencies of the left ventricular posterior wall (+0.59 ± 1.44 mm) and interventricular septal wall thickness (+0.59 ± 1.43) were observed in the non-adherence group. Left ventricular posterior wall thickness (coefficient: –0.254, p = 0.0376) and interventricular septal wall thickness (coefficient: –0.426, p = 0.0006) were more likely to be greater in the non-adherence group than in the good CPAP group. Patients in the non-adherence group with an apnea hypopnea index ≥30 had increased left ventricular posterior wall thickness (coefficient: –0.263, p = 0.0673) and interventricular septal wall thickness (coefficient: –0.450, p = 0.0011). In conclusion, appropriate CPAP therapy is an effective treatment for LVH in patients with T2DM and OSAS, especially for severe cases.
IN JAPAN, 21.4% of adults experience insomnia [1], and 14.9% report drowsiness during the day. In addition, 3.5% of men and 5.4% of women use sleeping pills [2], indicating the common occurrence of sleep disorders. In the Sleep and Food Registry in Kanagawa trial that included 4,000 patients with diabetes mellitus, 49% of participants had sleep disorders [3]. However, there is a paucity of studies with regard to obstructive sleep apnea syndrome (OSAS). The 2020 guidelines on sleep apnea syndrome define OSAS as an apnea hypopnea index (AHI) ≥15, affecting approximately 10% of women and 10–20% of men in Japan [4]. A previous study reported that 80.5% of patients with diabetes mellitus had OSAS [5]. While sleep disorders increase the risk of lifestyle diseases [6], eight major studies published between 2008 and 2022 that assessed sleep-related breathing disorders (SRBDs) reported independent associations between SRBD severity and glucose metabolism disorders, obesity, and age. However, few studies have examined the effects of SRBDs on the development and progression of complications of diabetes in patients with OSAS and type 2 diabetes mellitus (T2DM).
Diabetes mellitus and sleep apnea syndrome are risk factors for arteriosclerotic heart disease and heart failure. The AHI and hypoxemia are significantly associated with the presence of concentric hypertrophy in patients with OSAS. Moreover, patients with severe OSAS have increased arteriosclerosis indicators and a higher risk of fatal or non-fatal cardiovascular events [7]. OSAS and hypertension have a high rate of complications [8]. Hypertension associated with OSAS often presents with non-dipping nighttime early morning hypertension [9]. OSAS is associated with 70% of treatment-resistant hypertension, a condition in which blood pressure does not normalize even after administering three or more different antihypertensive drugs. Thus, OSAS is considered as one of the important causes of secondary hypertension [10]. Non-dipping and refractory hypertension are important risk factors for cardiovascular events. The antihypertensive effect of CPAP therapy on OSAS is mild yet significant. Antihypertensive effects were obtained both during the day and nighttime. At daytime, systolic and diastolic blood pressures were reduced by 2.2 ± 0.7 and 1.9 ± 0.6 mmHg, respectively. At nighttime, systolic and diastolic blood pressures were reduced by 3.8 ± 0.8 and 1.8 ± 0.6 mmHg , respectively [11]. A significant antihypertensive effect has also been confirmed in OSAS cases with treatment-resistant hypertension [12]. The risk of developing cardiovascular disease is high in OSAS cases; however, it may be reduced when receiving OSAS treatment [13]. Unfortunately, current randomized controlled trials investigating CPAP treatment in OSAS patients with cardiovascular disease showed no significant reduction in the risk of cardiovascular events [14].
Left ventricular hypertrophy (LVH) is considered a form of organ damage in the heart, and concentric hypertrophy is a predictor of an increased risk of cardiovascular events [15]. A short-term study reported that CPAP therapy improved LVH by inducing regression of left ventricular posterior wall thickness and interventricular septal wall thickness [16]; however, the long-term effects remain unclear. Despite the high rate of concomitant OSAS and diabetes mellitus, there is a paucity of studies regarding the effects of CPAP therapy on cardiac hypertrophy in patients with OSAS and diabetes mellitus. This study thus aimed to examine the effects of long-term CPAP therapy on LVH in patients with OSAS and T2DM by examining cardiac structural changes over a 3-year study period.
Materials and Methods
Study design
Patients with T2DM who were diagnosed with sleep apnea syndrome and treated with CPAP therapy were included in this study. Indications for CPAP therapy were based on the diagnosis and treatment of sleep apnea as covered by the national medical insurance [17]. The AHI used included the polysomnogram (PSG) AHI or respiratory event and oxygen desaturation index obtained from a simple apnea test using a portable sleep apnea test device (SAS2100, NIHON KOHDEN CORPORATION). Accordingly, the following cases were indicated for CPAP: if an AHI ≥40/h was recorded by the simple apnea test and symptoms suggesting sleep apnea syndrome were observed, if a suspected case of sleep apnea was observed, if an AHI ≥20/h was recorded by simple apnea test, or if an AHI ≥20/h was recorded in a PSG exam [17]. To assess the effects of CPAP therapy, the patients were divided into those who used CPAP for ≥4 h/day for ≥3 years since the initial diagnosis (good CPAP group) and those who used CPAP for <4 h/day (non-adherence group) since the initial diagnosis (Fig. 1). Study data will be published on the website. This study was performed according to the principles of the Declaration of Helsinki and was approved by the Yokohama City University Ethics Committee (approval number: B181000039). Informed consent was waived due to the retrospective nature of the study.
Patients who were visiting the clinics affiliated with the Minato Mirai group for sleep disorders and/or diabetes mellitus between January 1, 2015 and August 31, 2018 were included in this study. Patients aged ≥20 years, who had been diagnosed with insomnia, SRBD (based on the International Classification Sleep Disorders, Third Edition diagnostic classifications), and diabetes mellitus (based on the diabetes guidelines), were included in this study [4, 18]. Moreover, all included patients have had consultations in the hospital for >3 years after having been introduced to CPAP therapy. The information for each case was used at the time of CPAP therapy introduction and 3 years henceforth. The primary study outcome was the change in left ventricular posterior wall thickness after 3 years of CPAP therapy in patients with OSAS and diabetes mellitus. The secondary outcomes were factors affecting diabetes mellitus. Based on a previous study that reported a difference of 0.62 in the rate of change of left ventricular posterior wall thickness between groups with good and poor CPAP compliance [16], the required sample size was calculated to be 164 at a power of 80% and significance level of 5%. All variables recorded in this study were collected as part of routine medical care, and only existing data were used in this retrospective study.
Statistical analyses
Analyses of covariance for the primary outcome of the amount of change in the left ventricular posterior wall thickness and interventricular septal wall thickness, between years 0 and 3, were performed for the following variables: number of people using CPAP ≥4 h, age at CPAP therapy introduction, body-mass index (BMI) at CPAP therapy introduction, systolic blood pressure at CPAP introduction, number of people with glycated hemoglobin (HbA1c) levels <7% at CPAP therapy introduction, AHI, sex, number of people using sodium-glucose cotransporter-2 (SGLT-2) inhibitors, number of people not using biguanides, and left ventricular posterior wall thickness and interventricular septal wall thickness at CPAP therapy introduction. These factors were included in the covariance analysis due to the following rationale. LVH is associated with a decrease in oxygen saturation, although its direct involvement with AHI values has not been clarified [19]. The AHI value evaluates the apnea-hypopnea rate per hour; however, it does not directly evaluate oxygen saturation, which correlates with the severity of OSAS as defined by the AHI [20]. In addition, moderate or higher OSAS cases with an AHI ≥15 have been shown to reduce oxygen saturation [21]. Thus, the AHI value was selected because of its relationship with oxygen saturation. Further, increased systolic blood pressure [14] and obesity [14, 22] are independent risk factors for cardiac hypertrophy. SGLT-2 inhibitors [23] and biguanides [24] are used to treat diabetes, which induce the regression of cardiac hypertrophy. HbA1c <7% is a common target for diabetes management. Moreover, the baseline left ventricular posterior wall thickness and interventricular septal wall thickness may affect the final change in LVH, and thus, it was included as a factor.
All statistical analyses were performed using JMP Pro 15 (SAS Institute Japan Ltd, Tokyo, Japan). Statistical significance was set at p < 0.05.
Results
In total, 63 and 60 patients used CPAP for ≥4 and <4 h/day, respectively (Table 1). The mean CPAP usage times were 5.58 ± 1.23 and 1.03 ± 1.17 h/day in the good CPAP and non-adherence groups, respectively. The severity classification of OSAS was based on the clinical practice guideline 2020 for sleep apnea syndrome. However, since this study targeted cases with an AHI ≥20, the cases were classified as moderate (20 ≤ AHI < 30) and severe (AHI ≥30) [25]. Overall, there were 29 and 94 cases of moderate and severe OSAS, respectively.
Table 1
Patient characteristics
|
CPAP <4 h/day (n = 60) |
CPAP ≥4 h/day (n = 63) |
| CPAP use time (h/day) |
1.03 ± 1.17 |
5.58 ± 1.23 |
| Age (years) |
56.1 ± 11.0 |
60.2 ± 10.7 |
| Sex (male) |
37 |
43 |
| AHI (times/h) |
41.8 ± 14.9 |
46.2 ± 20.2 |
| Moderate OSAS* |
16 |
13 |
| Severe OSAS** |
44 |
50 |
| Diabetes history (years) |
8.3 ± 7.7 |
8.4 ± 10.2 |
| Alcohol use |
28 |
34 |
| Tobacco use |
26 |
32 |
| Dyslipidemia |
51 |
54 |
| Hypertension |
36 |
32 |
| SGLT-2 inhibitor use |
5 |
3 |
| Biguanide use |
35 |
33 |
| ARB/ACE use |
29 |
33 |
| Calcium antagonist use |
23 |
27 |
| Use of other antihypertensives |
8 |
8 |
Data are presented as means ± standard deviations or numbers.
Abbreviations: ACE = angiotensin-converting enzyme inhibitor; AHI = apnea hypopnea index; ARB = angiotensin II receptor blocker; CPAP = continuous positive airway pressure; SGLT-2 = sodium glucose cotransporter 2
* Moderate OSAS: 30 > AHI ≥ 20
** Severe OSAS: AHI ≥30
Table 2 shows the changes that occurred between the start of drug therapy for medical conditions, including diabetic neuropathy, diabetic nephropathy, cardiovascular disorder, cerebrovascular disorder, malignant tumor, diabetes, and dyslipidemia, and the 3-year timepoint. Meanwhile, Table 3 shows the changes in the parameters, including BMI, blood pressure, blood test, urine test, physiological test, and echocardiography, at the start, 3-year timepoint, and during the study period. The 3-year changes in the CPAP <4 h/day group were as follows: LVMI (men) (9.7 ± 24.6 g/m2), LVMI (women) (3.6 ± 19.3g/m2), left ventricular posterior wall thickness (0.59 ± 1.44 mm), and interventricular septal wall thickness (0.59 ± 1.43 mm); all values increased. However, all values decreased in the CPAP ≥4 h/day group: LVMI (men) (–7.6 ± 22.2 g/m2), LVMI (women) (–4.7 ± 30.2 g/m2), left ventricular posterior wall thickness (–0.30 ± 1.19 mm), and interventricular septal wall thickness (–0.48 ± 1.22 mm).
Table 2
Changes in patient characteristics (diabetes complications, comorbidities, medicines)
|
CPAP <4 h/day (n = 60) |
CPAP ≥4 h/day (n = 63) |
| Baseline |
Study end |
Baseline |
Study end |
| Diabetic neuropathy |
25 |
26 |
30 |
32 |
| Diabetic retinopathy (no/simple/pre-proliferative/proliferative) |
46/7/2/5 |
46/7/2/5 |
52/9/1/1 |
51/10/1/1 |
| Heart disease* |
4 |
6 |
10 |
14 |
| Cerebrovascular disease |
11 |
11 |
14 |
14 |
| Malignant tumor |
0 |
1 |
5 |
5 |
| Insulin (units) |
6.8 ± 16.5 |
8.5 ± 19.8 |
3.1 ± 8.1 |
3.4 ± 9.5 |
| GLP-1 agonist use |
1 |
2 |
1 |
3 |
| DPP4 inhibitor use |
30 |
33 |
24 |
30 |
| α-Glucosidase inhibitor use |
5 |
5 |
10 |
9 |
| Sulfonylurea use |
13 |
15 |
13 |
12 |
| Glinide use |
5 |
5 |
6 |
8 |
| Thiazolidine use |
6 |
9 |
2 |
5 |
| Statin use |
35 |
36 |
41 |
42 |
| Ezetimibe use |
4 |
4 |
2 |
2 |
| Fibrate use |
6 |
6 |
8 |
8 |
| Icosapentate use |
8 |
8 |
21 |
22 |
| Omega-3 fatty acid use |
1 |
1 |
1 |
1 |
Data are shown as means ± standard deviations.
Abbreviations: DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1
* At the study end, four patients in the good CPAP group had atrial fibrillation. In the control group, one patient had angina and one had atrial fibrillation.
Table 3
Changes in patient characteristics (physical findings, Vital sign, Blood test, Urinalysis, physiological function test)
|
CPAP <4 h/day (n = 60) |
CPAP ≥4 h/day (n = 63) |
| Baseline |
Study end |
Change |
Baseline |
Study end |
Change |
| BMI (kg/m2) |
27.1 ± 5.8 |
27.1 ± 5.6 |
–0.04 ± 1.45 |
25.5 ± 4.5 |
25.9 ± 4.1 |
+0.36 ± 1.37 |
| SBP (mmHg) |
133.1 ± 13.1 |
132.4 ± 14.2 |
–0.7 ± 11.5 |
130.9 ± 11.0 |
128.0 ± 11.8 |
–3.0 ± 12.3 |
| DBP (mmHg) |
78.9 ± 11.2 |
78.4 ± 9.4 |
–0.6 ± 10.5 |
75.7 ± 9.7 |
74.3 ± 11.4 |
–1.4 ± 10.1 |
| Hb (g/dL) |
14.3 ± 1.5 |
14.3 ± 1.4 |
–0.02 ± 0.79 |
14.2 ± 1.4 |
14.0 ± 1.4 |
–0.13 ± 0.77 |
| U-ALB (mg/dL) |
63.1 ± 82.3 |
56.3 ± 73.3 |
–6.8 ± 61.6 |
56.5 ± 63.7 |
59.1 ± 62.0 |
+2.6 ± 53.2 |
| AST (U/L) |
28.7 ± 15.0 |
28.8 ± 19.5 |
+0.2 ± 15.4 |
26.3 ± 14.3 |
25.0 ± 8.3 |
–1.3 ± 12.0 |
| ALT (U/L) |
35.6 ± 24.9 |
32.5 ± 20.3 |
–3.1 ± 18.0 |
29.4 ± 21.2 |
28.1 ± 16.7 |
–1.3 ± 13.2 |
| γGTP (U/L) |
55.6 ± 79.3 |
55.9 ± 84.6 |
+0.3 ± 28.5 |
49.3 ± 65.2 |
44.2 ± 51.4 |
–5.1 ± 30.6 |
| Cre (mg/dL) |
0.78 ± 0.27 |
0.83 ± 0.32 |
+0.05 ± 0.11 |
0.81 ± 0.19 |
0.84 ± 0.18 |
+0.03 ± 0.12 |
| eGFR (mL/min/1.73 m2) |
77.7 ± 17.9 |
70.6 ± 18.8 |
–7.2 ± 11.1 |
72.8 ± 16.3 |
69.3 ± 17.7 |
–3.5 ± 10.6 |
| UA (mg/dL) |
5.1 ± 1.2 |
5.3 ± 1.2 |
+0.1 ± 0.8 |
5.1 ± 1.2 |
5.2 ± 1.1 |
+0.1 ± 1.0 |
| BG (mg/dL) |
137.7 ± 45.6 |
143.3 ± 53.8 |
+5.6 ± 55.9 |
134.7 ± 45.8 |
131.7 ± 49.0 |
–3.0 ± 60.0 |
| HbA1c (%) |
6.82 ± 0.87 |
6.98 ± 0.98 |
+0.16 ± 0.63 |
6.63 ± 0.88 |
6.76 ± 0.78 |
+0.12 ± 0.66 |
| CPR index |
2.00 ± 1.17 |
2.37 ± 1.50 |
+0.32 ± 1.11 |
1.71 ± 0.77 |
2.02 ± 1.25 |
–0.07 ± 0.95 |
| T-cho (mg/dL) |
192.6 ± 39.7 |
191.8 ± 31.0 |
–0.8 ± 32.3 |
182.0 ± 41.1 |
189.8 ± 31.1 |
+7.8 ± 41.7 |
| LDL-C (mg/dL) |
105.3 ± 25.3 |
105.5 ± 24.5 |
+0.2 ± 26.7 |
105.1 ± 32.4 |
104.2 ± 27.2 |
–0.8 ± 35.2 |
| HDL-C (mg/dL) |
54.2 ± 14.3 |
55.1 ± 11.7 |
+0.9 ± 10.3 |
54.5 ± 17.1 |
53.4 ± 13.4 |
–1.1 ± 11.2 |
| TG (mg/dL) |
181.2 ± 158.3 |
150.2 ± 74.9 |
–31.0 ± 139.3 |
154.3 ± 95.6 |
162.9 ± 100.4 |
+8.7 ± 96.2 |
| ABI (right) |
1.14 ± 0.12 |
1.13 ± 0.11 |
+0.001 ± 0.100 |
1.15 ± 0.12 |
1.13 ± 0.10 |
+0.001 ± 0.111 |
| ABI (left) |
1.13 ± 0.11 |
1.13 ± 0.12 |
–0.001 ± 0.10 |
1.11 ± 0.09 |
1.12 ± 0.08 |
+0.014 ± 0.10 |
| IMT (mm) (right) |
0.83 ± 0.13 |
0.84 ± 0.15 |
+0.008 ± 0.118 |
0.87 ± 0.13 |
0.87 ± 0.15 |
–0.001 ± 0.098 |
| (left) |
0.86 ± 0.14 |
0.87 ± 0.16 |
+0.007 ± 0.118 |
0.86 ± 0.14 |
0.88 ± 0.15 |
+0.011 ± 0.106 |
| LVMI (g/m2) (men) |
102.7 ± 24.8 |
112.4 ± 30.3 |
+9.7 ± 24.6 |
114.5 ± 27.0 |
106.9 ± 22.2 |
–7.6 ± 22.2 |
| (women) |
106.3 ± 27.7 |
109.8 ± 25.3 |
+3.6 ± 19.3 |
107.4 ± 30.2 |
102.7 ± 25.0 |
–4.7 ± 30.2 |
| RWT |
0.44 ± 0.08 |
0.47 ± 0.10 |
+0.02 ± 0.09 |
0.46 ± 0.08 |
0.45 ± 0.07 |
–0.01 ± 0.08 |
| AD (mm) |
29.6 ± 3.3 |
30.6 ± 3.7 |
+0.91 ± 3.23 |
31.0 ± 3.8 |
32.0 ± 4.3 |
+1.00 ± 3.34 |
| LAD (mm) |
35.3 ± 4.4 |
35.9 ± 4.4 |
+0.70 ± 3.21 |
36.3 ± 4.9 |
36.4 ± 4.9 |
+0.11 ± 3.68 |
| IVST (mm) |
10.7 ± 1.7 |
11.2 ± 1.9 |
+0.59 ± 1.43 |
11.2 ± 1.8 |
10.7 ± 1.6 |
–0.48 ± 1.22 |
| LVPWth (mm) |
10.5 ± 1.6 |
11.0 ± 1.9 |
+0.59 ± 1.44 |
11.0 ± 1.5 |
10.7 ± 1.5 |
–0.30 ± 1.19 |
| LVEDD (mm) |
47.9 ± 5.2 |
47.7 ± 5.9 |
–0.21 ± 5.19 |
48.0 ± 5.4 |
48.0 ± 4.8 |
+0.02 ± 5.59 |
| LVESD (mm) |
29.1 ± 5.2 |
30.0 ± 5.5 |
+0.82 ± 5.95 |
28.4 ± 5.4 |
29.8 ± 4.5 |
+1.36 ± 5.50 |
| SV (mL) |
74.8 ± 18.2 |
68.6 ± 19.8 |
–6.19 ± 26.3 |
77.4 ± 18.1 |
73.8 ± 16.4 |
–3.60 ± 20.1 |
| LVFS (mm) |
39.8 ± 4.9 |
38.1 ± 5.9 |
–1.73 ± 6.94 |
40.3 ± 8.0 |
38.3 ± 5.5 |
–1.99 ± 8.76 |
| EF (mm) |
69.9 ± 6.0 |
67.5 ± 6.4 |
–2.33 ± 7.99 |
71.0 ± 8.0 |
68.0 ± 7.0 |
–3.02 ± 9.20 |
Data are shown as means ± standard deviations.
Abbreviations: AD, aortic diameter; BG, blood glucose; BMI, body mass index; Cre, creatinine; DBP, diastolic blood pressure; EF, ejection fraction; HDL-C, high-density lipoprotein cholesterol; IMT, intima media thickness; IVST, interventricular septum thickness; LAD, left atrial dimension; LDL-C, low-density lipoprotein cholesterol, LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter; LVFS, left ventricular fractional shortening; LVMI, left ventricular mass index; LVPWth, thickness of left ventricular posterior wall; RWT, relative wall thickening; SBP, systolic blood pressure; SV, stroke volume; T-cho, total cholesterol; TG, triglyceride; U-ALB, urine albumin
The results of analysis of covariance for the left ventricular posterior wall thickness and interventricular septal wall thickness is shown in Table 4. Good CPAP use (≥4 h/day) was associated with a significant suppression of the increase in left ventricular posterior wall thickness (coefficient: –0.254, p = 0.0376) and interventricular septal wall thickness (coefficient: –0.426, p = 0.0006). A similar analysis of covariance was also performed on the left ventricular mass index and relative wall thickening. The result showed that good CPAP use (≥4 h/day) resulted in a significant regression of the left ventricular mass index in men (coefficient: –6.088, p = 0.0199) (Supplemental Tables 1 and 2).
Table 4
Analysis of covariance for thickness of left ventricular posterior wall and interventricular septal wall
| Changes in thickness of LVPWth |
Changes in IVST |
|
Coefficient |
95% CI |
p |
|
Coefficient |
95% CI |
p |
| CPAP use ≥4 h/day |
–0.254 |
–4.926, –0.015 |
0.0376 |
CPAP use ≥4 h/day |
–0.426 |
–0.665, –0.188 |
0.0006 |
| Age at baseline (years) |
–0.014 |
–0.040, 0.012 |
0.2869 |
Age at baseline (years) |
–0.004 |
–0.030, 0.022 |
0.7542 |
| BMI baseline (kg/m2) |
0.021 |
–0.036, 0.078 |
0.4683 |
BMI baseline (kg/m2) |
0.006 |
–0.051, 0.063 |
0.8423 |
| SBP at baseline (mmHg) |
0.022 |
0.002, 0.043 |
0.0310 |
SBP at baseline (mmHg) |
0.019 |
–0.001, 0.039 |
0.0654 |
| HbA1c <7% baseline |
–0.157 |
–0.403, 0.090 |
0.2106 |
HbA1c <7% at baseline |
–0.046 |
–0.292, 0.200 |
0.7129 |
| AHI at baseline |
–0.005 |
–0.019, 0.009 |
0.4722 |
AHI at baseline |
–0.003 |
–0.017, 0.011 |
0.6756 |
| Sex (male) |
0.314 |
0.061, 0.566 |
0.0154 |
Sex (male) |
0.306 |
0.054, 0.558 |
0.0178 |
| Use of SGLT-2 inhibitors |
–0.132 |
–0.603, 0.340 |
0.5813 |
Use of SGLT-2 inhibitors |
–0.307 |
–0.782, 0.168 |
0.2025 |
| Use of biguanides |
–0.116 |
–0.347, 0.116 |
0.3238 |
Use of biguanides |
–0.012 |
–0.243, 0.220 |
0.9212 |
| LVPWth at baseline (mm) |
–0.372 |
–0.537, –0.207 |
<0.0001 |
IVST at baseline (mm) |
–0.351 |
–0.494, –0.208 |
<0.0001 |
Abbreviations: AHI, apnea hypopnea index; BMI, body mass index; CI, confidence interval; CPAP, continuous positive airway pressure; HbA1c, hemoglobin A1c; IVST, interventricular septal wall thickness; LVPWth, left ventricular posterior wall thickness; SBP, systolic blood pressure; SGLT-2, sodium glucose transporter 2
Patients were further divided into groups with an AHI ≥30 (n = 94) or <30 (n = 29). Among patients with an AHI <30, good CPAP use (≥4 h/day) has no significant changes in the left ventricular posterior wall thickness (coefficient: –0.076; p = 0.7928) or in the interventricular septal wall thickness (coefficient: –0.345: p = 0.2908) (Table 5).
Table 5
Analysis of covariance for thickness of left ventricular posterior wall and interventricular septal wall in cases with AHI <30
| Changes in thickness of LVPWth |
Changes in IVST |
|
Coefficient |
95% CI |
p |
|
Coefficient |
95% CI |
p |
| CPAP use ≥4 h/day |
–0.076 |
–0.669, 0.518 |
0.7928 |
CPAP use ≥4 h/day |
–0.345 |
–1.007, 0.318 |
0.2908 |
| Age at baseline (years) |
–0.033 |
–0.106, 0.039 |
0.3491 |
Age at baseline (years) |
–0.013 |
–0.093, 0.067 |
0.7424 |
| BMI at baseline (kg/m2) |
0.001 |
–0.166, 0.169 |
0.9882 |
BMI at baseline (kg/m2) |
–0.101 |
–0.282, 0.080 |
0.2569 |
| SBP at baseline (mmHg) |
0.025 |
–0.019, 0.069 |
0.2546 |
SBP at baseline (mmHg) |
0.021 |
–0.026, 0.068 |
0.3529 |
| HbA1c <7% baseline |
0.066 |
–0.545, 0.677 |
0.8243 |
HbA1c <7% at baseline |
–0.047 |
–0.702, 0.608 |
0.8827 |
| Sex (male) |
0.374 |
–0.189, 0.936 |
0.1809 |
Sex (male) |
0.485 |
–0.112, 1.082 |
0.1056 |
| Use of SGLT-2 inhibitors* |
|
|
|
Use of SGLT-2 inhibitors* |
|
|
|
| Use of biguanides |
–0.053 |
–0.546, 0.652 |
0.8555 |
Use of biguanides |
0.130 |
–0.781, 0.520 |
0.6805 |
| LVPWth at baseline (mm) |
–0.267 |
–0.704, 0.169 |
0.2153 |
IVST at baseline (mm) |
–0.119 |
–0.480, 0.242 |
0.4999 |
Abbreviations: AHI = apnea hypopnea index; BMI, body mass index; CI, confidence interval; CPAP, continuous positive airway pressure; HbA1c, hemoglobin A1c; IVST, interventricular septum thickness; LVPWth, thickness of left ventricular posterior wall; SBP, systolic blood pressure; SGLT-2, sodium glucose transporter 2
* No patients in the AHI <30 group used SGLT-2 inhibitors
Among patients with an AHI ≥30, good CPAP use (≥4 h/day) has significant changes in the interventricular septal wall thickness (coefficient: –0.450: p = 0.0011), but not in the left ventricular posterior wall thickness (coefficient: –0.263; p = 0.0673) (Table 6).
Table 6
Analysis of covariance for the thickness of left ventricular posterior wall and interventricular septal wall in cases with AHI ≥30
| Changes in thickness of LVPWth |
Changes in IVST |
|
Coefficient |
95% CI |
p |
|
Coefficient |
95% CI |
p |
| CPAP use ≥4 h/day |
–0.263 |
–0.545, 0.019 |
0.0673 |
CPAP use ≥4 h/day |
–0.450 |
–0.714, –0.186 |
0.0011 |
| Age at baseline (years) |
–0.012 |
–0.042, 0.018 |
0.4231 |
Age at baseline (years) |
–0.004 |
–0.032, 0.024 |
0.7595 |
| BMI at baseline (kg/m2) |
0.022 |
–0.039, 0.083 |
0.4708 |
BMI at baseline (kg/m2) |
0.022 |
–0.035, 0.079 |
0.4420 |
| SBP at baseline (mmHg) |
0.024 |
–0.001, 0.049 |
0.0635 |
SBP at baseline (mmHg) |
0.017 |
–0.006, 0.040 |
0.1481 |
| HbA1c <7% at baseline |
–0.220 |
–0.502, 0.062 |
0.1244 |
HbA1c <7% at baseline |
–0.075 |
–0.341, 0.192 |
0.5779 |
| Sex (male) |
0.245 |
–0.043, 0.533 |
0.0948 |
Sex (male) |
0.259 |
–0.013, 0.531 |
0.0622 |
| Use of SGLT-2 inhibitors |
–0.117 |
–0.610, 0.376 |
0.6378 |
Use of SGLT-2 inhibitors |
–0.298 |
–0.769, 0.172 |
0.2110 |
| Use of biguanides |
–0.159 |
–0.428, 0.110 |
0.2426 |
Use of biguanides |
0.037 |
–0.218, 0.292 |
0.7744 |
| LVPWth at baseline (mm) |
–0.382 |
–0.571, –0.193 |
0.0001 |
IVST at baseline (mm) |
–0.351 |
–0.560, –0.239 |
<0.0001 |
Abbreviations: AHI, apnea hypopnea index; BMI, body mass index; CI, confidence interval, CPAP = continuous positive airway pressure; HbA1c = hemoglobin A1c; IVST = interventricular septum thickness; LVPWth = thickness of left ventricular posterior wall; SBP = systolic blood pressure; SGLT-2 = sodium glucose transporter 2
Discussion
This retrospective analysis of patients with concomitant T2DM and OSAS revealed that the use of CPAP may regress the thickness of the left ventricular posterior and interventricular septal walls, leading to LVH regression. In addition, a sub-analysis showed that when CPAP was used appropriately, the group with an AHI <30 did not exhibit significant regression of the thickness of the left ventricular posterior or interventricular septal wall, while severe OSAS cases included in the group with an AHI ≥30 exhibited significant regression of interventricular septal wall thickness.
The findings of this study suggest that the use of appropriate CPAP therapy may be effective for LVH in patients with T2DM and OSAS with an AHI ≥20, which are indications for CPAP therapy in Japan [17] and that reduction of regressing interventricular septal wall thickness may be achieved in severe OSAS cases (AHI ≥30).
In discussing the results of this study, we will first describe the involvement of OSAS and T2DM in LVH. Several studies have reported LVH as an independent predictor of cardiovascular events [26], and the thickness of the left ventricular posterior and interventricular septal walls were used as indicators [27].
As previously described, OSAS is associated with hypertension. In addition, both coexist with several independent confounding factors, such as diabetes, obesity, and age [28, 29], which have been reported to be associated with LVH and cardiovascular disease [30]. OSAS has been reported as an independent risk factor for cardiac hypertrophy [31], which causes superoxide [32] and angiotensin 2 production, as well as aldosterone activity [33] based on hypoxemia. Both are implicated in left ventricular remodeling. Moreover, hypertension has been reported to independently cause LVH [34], nocturnal hypertension is associated with LVH, and the tendency is remarkable in non-dipping type nocturnal hypertension [35]. T2DM is a risk factor for cardiovascular disease and cardiac hypertrophy [36-39], although the full picture has not been clearly elucidated. However, a recently published prospective cohort study found that T2DM did not affect the incidence of LVH and that concomitant risks, such as hypertension and obesity, have a greater impact on the development of LVH in diabetes patients [40].
Next, we will discuss LVH regression with the application of CPAP therapy, including the mechanism. A previous study reported that 3 months of CPAP therapy resulted in improved cardiac hypertrophy in patients without diabetes [16]. However, no studies to date have described the therapeutic effects of CPAP therapy on LVH in patients with T2DM. First, the effect of CPAP therapy will be described. CPAP therapy is generally expected to suppress the onset of hypertension [41] and to improve subjective daytime drowsiness [42] when used for an average of ≥4 h daily. Current studies have reported on the antihypertensive effects on daytime and nocturnal hypertension, as well as treatment-resistant hypertension [11], and improvement in oxygen saturation [43]. At present, there is no clear consensus on the effect of CPAP therapy alone on glucose metabolism disorders.
In our study, we performed an analysis of covariance that included CPAP therapy use for ≥4 ha day and found that appropriate CPAP therapy resulted in significant regression in both left ventricular posterior wall thickness and interventricular septal wall thickness. All patients included in this study had an AHI ≥20, which is likely to be complicated by a decreased oxygen saturation [22]. Since appropriate use of CPAP therapy resulted in improved oxygen saturation, it is likely that improved oxygen saturation contributed to LVH regression in this study.
To investigate the effects of CPAP therapy on blood pressure and blood glucose levels over a 3-year period, we conducted an analysis in which the basal systolic blood pressure value was changed to the amount of change in systolic blood pressure, and the number of patients with HbA1c <7% at the start of CPAP therapy was changed to the amount of change in HbA1c. Systolic blood pressure (coefficient: 0.004: p = 0.6930) and HbA1c levels (coefficient: 0.200: p = 0.273) were not significant enough to affect the left ventricular posterior wall thickness. Concomitantly, although both systolic blood pressure (coefficient: 0.015: p = 0.1459) and HbA1c (coefficient: –0.118: p = 0.5088) were not significant enough to affect the interventricular septal wall thickness. Thus, changes in blood pressure and HbA1c due to CPAP therapy had minimal effect on LVH.
Considering the fact that the antihypertensive effect of CPAP is significant but minor [11], that nocturnal hypertension correlates with the severity in OSAS even in cases with normal ambulatory blood pressure [44], and that nocturnal hypertension is strongly related to LVH as mentioned above, we believe that the lack of a significant relationship between blood pressure change in this outpatient measurement and LVH is consistent. The effect of CPAP therapy on blood glucose levels has not been clarified. Our results showing no significant relationship between the change in HbA1c and LVH is consistent with those of previous reports.
In addition, we describe a discussion of the therapeutic effect of CPAP therapy on the severity of OSAS obtained in the subgroup analysis. Our study examined changes in LVH in severe and less severe OSAS and found that only severe OSAS showed a significant regression of interventricular septal wall thickness. Meanwhile, the therapeutic effect of CPAP therapy on nocturnal hypertension in OSAS cases was significantly reduced in patients with OSAS with an AHI ≥15, but not in those with an AHI <15 [45]. It has also been reported that the severity of OSAS correlates with a decreased oxygen saturation [20]. Thus, the results of this subgroup analysis suggest that the improvement of nocturnal hypertension and oxygen saturation may contribute to the mechanism of LVH regression induced by CPAP therapy. Therefore, the regression of LVH in OSAS patients with T2DM in our study may be due to the improvement of nocturnal hypertension and hypoxemia, with appropriate use of CPAP, thereby preventing the increase in LVH. In addition, we considered the possibility that the therapeutic effect of CPAP therapy on LVH may be more pronounced in severe OSAS. However, changes in oxygen saturation and nocturnal hypertension could not be measured directly and it is more important to manage the associated risk factors for the effects of T2DM on LVH. Therefore, although the effect of CPAP therapy per se on glucose metabolism disorders is unclear, it is possible that it may be effective in suppressing LVH. Within this premise, appropriate CPAP therapy use may be effective for LVH in OSAS patients with T2DM.
The risk of progressing to symptomatic heart failure or death is increased in patients with concomitant OSAS and T2DM, who do not receive appropriate long-term care. The results of this study indicate that proactively administering CPAP therapy may help control LVH and improve patient prognosis. However, several studies have described a low frequency of CPAP use and patients terminating CPAP against the recommendations of providers. CPAP compliance rates have been reported as high as 43–53% [46, 47]. In this regard, educating patients regarding the proper use of CPAP therapy and its benefits for prognosis may lead to better CPAP compliance.
This study has some limitations. We did not assess the effects of CPAP therapy on previously reported LVH and cardiovascular risk factors, including poor blood pressure control [48], obesity [22, 49], oxygen saturation [32, 33, 43], elevated nocturnal norepinephrine, and nocturnal hypertension [44]. In addition, the number of participants included in this study was small and below the required sample size. There was a significant difference in left ventricular posterior wall thickness, and interventricular septal wall thickness improvement between the groups. Therefore, the sample size was sufficient to assess the effects of CPAP therapy in this study. Lastly, this was a retrospective study. To avoid selection bias and to examine the therapeutic effects of CPAP more accurately, prospective studies should be conducted.
In conclusion, this study demonstrated that patients with OSAS and T2DM who received appropriate CPAP therapy had significant improvements in cardiac hypertrophy after 3 years. Aggressive CPAP therapy is recommended for patients with severe OSAS (AHI ≥30). The therapeutic effects of CPAP on cardiac hypertrophy should be investigated in future randomized controlled trials examining nocturnal hypertension and long-term prognoses associated with cardiovascular events.
Abbreviations
AHI, apnea hypopnea index; API, apnea-hypopnea index; BMI, body mass index; CPAP, continuous positive airway pressure; eGFR, estimated glomerular filtration rate; LVH, left ventricular hypertrophy; OR, odds ratio; OSAS, obstructive sleep apnea syndrome; PSG, polysomnography; SAS, sleep apnea syndrome; SRBDs, sleep-related breathing disorders
Acknowledgments
We would like to thank Miwako Seki and Yoshiko Terashima for their contributions to this study and Editage (www.editage.com) for the English language editing.
Disclosures
None of the authors have any potential conflicts of interest associated with this research.
Supplemental Table 1
Analysis of covariance for LVMI in men and women
| Changes in LVMI in men |
Changes in LVMI in women |
|
Coefficient |
95% CI |
p |
|
Coefficient |
95% CI |
p |
| CPAP use ≥4 h/day |
–6.088 |
–11.182, –0.994 |
0.0199 |
CPAP use ≥4 h/day |
–5.153 |
–12.794, 2.488 |
0.1795 |
| Age at baseline (years) |
0.189 |
–0.314, 0.691 |
0.4571 |
Age at baseline (years) |
0.430 |
–0.768, 1.628 |
0.4707 |
| BMI at baseline (kg/m2) |
0.760 |
–0.476, 1.996 |
0.2242 |
BMI at baseline (kg/m2) |
0.719 |
–1.009, 2.448 |
0.4035 |
| SBP at baseline (mmHg) |
0.358 |
–0.058, 0.774 |
0.0904 |
SBP at baseline (mmHg) |
–0.378 |
–1.107, 0.351 |
0.2996 |
| HbA1c <7% at baseline |
–0.416 |
–6.018, 5.187 |
0.8827 |
HbA1c <7% at baseline |
3.133 |
–4.597, 10.863 |
0.4159 |
| AHI at baseline |
–0.069 |
–0.344, 0.206 |
0.6171 |
AHI at baseline |
–0.161 |
–0.802, 0.480 |
0.6123 |
| Use of SGLT-2 inhibitors |
5.966 |
–14.470, 2.538 |
0.1662 |
Use of SGLT-2 inhibitors* |
|
|
|
| Use of biguanides |
2.266 |
–7.194, 2.662 |
0.3623 |
Use of biguanides |
8.656 |
0.774, 16.539 |
0.0323 |
| LVMI at baseline (gm/m2) |
–0.448 |
–0.643, –0.252 |
<0.0001 |
LVMI at baseline (gm/m2) |
–0.444 |
–0.715, –0.174 |
0.0020 |
Abbreviations: AHI, apnea hypopnea index; BMI, body mass index; CI, confidence interval; CPAP, continuous positive airway pressure; HbA1c, hemoglobin A1c; LVMI, left ventricular mass index; SBP, systolic blood pressure; SGLT-2, sodium glucose cotransporter 2
* No women used SGLT-2 inhibitors in this study
Supplemental Table 2
Analysis of covariance for RWT
|
Coefficient |
95% CI |
p |
| CPAP use ≥4 h/day |
–0.013 |
–0.028, 0.002 |
0.0932 |
| Age at baseline (years) |
–0.009 × 10–1 |
–0.003, 0.001 |
0.2718 |
| BMI at baseline (kg/m2) |
–0.008 × 10–1 |
–0.004, 0.003 |
0.6405 |
| SBP at baseline (mmHg) |
0.001 |
0.008 × 10–1, 0.003 |
0.0375 |
| HbA1c <7% at baseline |
–0.004 |
–0.020, 0.011 |
0.5965 |
| AHI at baseline |
–0.006 × 10–3 |
–0.008 × 10–1, –0.001 |
0.8993 |
| Sex (male) |
0.010 |
–0.006, 0.026 |
0.2294 |
| Use of SGLT-2 inhibitors |
0.004 |
–0.026, 0.006 |
0.8083 |
| Use of biguanides |
–0.009 |
–0.024, 0.005 |
0.2157 |
| RWT at baseline (gm/m2) |
–0.545 |
–0.737, –0.352 |
<0.0001 |
Abbreviations: AHI, apnea hypopnea index; BMI, body mass index; CI, confidence interval, CPAP, continuous positive airway pressure; HbA1c, hemoglobin A1c; RWT, relative wall thickening; SBP, systolic blood pressure; SGLT-2, sodium glucose cotransporter 2
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