Obesity metabolic and hormonal disorders associated with obstructive sleep apnea and their impact on the risk of cardiovascular events.

OBJECTIVE: To analyze metabolic and hormonal disorders resulting from the association between obesity and obstructive sleep apnea (OSA) syndrome that predispose to cardiovascular diseases and investigate the clinical benefits obtained from treatment approaches for both conditions. METHODS: A literature review between 1997 and 2017 was conducted in the PubMed search database. RESULTS: Obesity is the most important risk factor for OSA, and the progressive increase in its prevalence also affects OSA incidence. In addition, OSA may aggravate weight gain and obesity comorbidities. Both conditions lead to an increase in the risk of cardiovascular events and mortality. The gold standard treatment for moderate to severe OSA is CPAP, but significant reduction in major cardiovascular events was not observed in clinical trials. Body weight reduction appears effective to improve OSA, as long as it is maintained. Lifestyle modifications and drug therapy seem to be the preferred approach to treat obesity, but in severe obesity and moderate to severe OSA, bariatric surgery is probably the most adequate treatment. CONCLUSIONS: Weight control is essential to decrease the risk of cardiovascular events and mortality potentially linked to both obesity and OSA. CPAP seems to treat only OSA without decreasing these risks. Other treatment strategies are lifestyle modifications and drug therapy, which need further investigation as well as bariatric surgery for severe cases.

IGF-1 Levels are Inversely Associated With Metabolic Syndrome in Obstructive Sleep Apnea.

STUDY OBJECTIVES: This study examined insulin-like growth factor-1 (IGF-1) production and its association with the metabolic syndrome (MS) in men with obstructive sleep apnea (OSA). METHODS: In total, 47 overweight and obese men who had been referred for suspected OSA underwent polysomnography and were classified based on the apnea-hypopnea index (AHI) into three groups: no OSA, < 5 events/h (n = 11); mild OSA, ≥ 5 to < 15 events/h (n = 8); and moderate-severe OSA, ≥ 15 events/h (n = 28). The assessment of the somatotropic axis function included IGF-1 measurement. MS was diagnosed according to the National Cholesterol Education Program guidelines. RESULTS: IGF-1 level in the moderate-severe OSA group was lower than in the no-OSA group (156.8 ± 54.3 µg/L versus 225.5 ± 80.5 µg/L; p = 0.013). IGF-1 level was negatively correlated with body mass index, waist circumference (WC), AHI, and sleep duration with oxygen (O2) saturation < 90% and positively correlated with the average and minimum O2 saturation (p = 0.027). In a multivariable linear regression, considering WC and minimum O2 saturation as independent variables, only the minimum O2 saturation was a predictor of low IGF-1 levels. The proportions of patients with MS were different between the three groups (18.2% in no OSA; 25% in mild OSA, and 57.1% in moderate-severe OSA; p = 0.047). Furthermore, in the lowest tertile of IGF-1 value, 66.7% of patients were affected by MS (p = 0.049). Hemoglobin (Hb)A1c correlated negatively with the minimum O2 saturation and IGF-1 levels. However, in multivariable linear regression only IGF-1 levels were a predictor of HbA1c levels. CONCLUSION: The occurrence of OSA is associated with a reduction in IGF-1 levels. IGF-1 alterations in OSA also seem to be associated with a higher prevalence of MS.

Willingness to pay as patient preference to bariatric surgery.

BACKGROUND: An obesity epidemic is spreading worldwide. In addition to comorbidities, social and emotional problems contribute to reduce the quality of life (QoL) of obese people. Considering the heterogeneity of outcomes from clinical and surgical approaches, it is recommended that severely obese patients participate in their treatment decisions. This study evaluated preferences of severely obese patients for obesity surgical treatment using the willingness to pay (WTP) and to assess the impact of the presence of some clinical disorders, socioeconomic conditions and QoL on their decisions. METHODS: The selected patients were invited to answer the WTP questionnaire using two formats of contingent valuation questions: dichotomous choice (yes/no) and a bidding game. The answers were correlated with clinical features, QoL assessed by the SF-36 and the Moorehead-Ardelt Quality of Life Questionnaire II, Brazilian socioeconomic classification, and family and personal incomes. RESULTS: The group of patients who accepted the first bid was older and had higher frequency of sleep apnoea when compared to those who rejected the offer. A significant correlation between the bidding game value and family income was found (r = 0.28; P < 0.02). In the logistic regression model, socioeconomic classification and sleep apnoea were shown to be independently associated with acceptance the bid. CONCLUSIONS: Sleep apnoea was the comorbidity that most influenced the acceptance in dichotomous choice for bariatric surgery, probably due to the deleterious effects on daily activities induced by sleep disturbances. Our findings also suggest that the frequency of surgical procedures is below the preference of the obese population in Brazil.

Obstructive sleep apnea predisposes to nonalcoholic Fatty liver disease in patients with polycystic ovary syndrome.

OBJECTIVE: Some studies have shown a higher prevalence of nonalcoholic fatty liver disease (NAFLD) and obstructive sleep apnea (OSA) in patients with polycystic ovary syndrome (PCOS). The objective of this study was to assess NAFLD in PCOS women with and without OSA. A possible role of high serum androgen levels in the development of OSA in PCOS women was also investigated. METHODS: Biochemical, hormonal, and polysomnography parameters were determined in 38 premenopausal PCOS patients. NAFLD was evaluated by ultrasound. Testosterone was measured by an immunoassay. RESULTS: Serum androgen levels and the prevalence of NAFLD (83.3% vs. 26.9%; P<.001) were higher in patients with OSA than those without OSA. The mean apnea-hypopnea index (AHI) was higher in patients with NAFLD than in those without NAFLD (16.87 events [ev]/h vs. 1.57 ev/h; P<.002). On multivariate logistic regression, where body mass index ≥30 kg/m2, homeostasis model assessment for insulin resistance ≥2.7, and OSA (AHI ≥5 ev/h) were independent variables, only OSA was an independent predictor of NAFLD (odds ratio [OR], 7.63; P = .044). Free testosterone levels ≥1.07 ng/dL were also independently associated with OSA (OR, 8.18; P = .023). CONCLUSION: In PCOS women, the occurrence of OSA strongly predisposes them to development of NAFLD and a worse metabolic profile; hence, treatment of OSA might be beneficial for NAFLD.

Consequences of obstructive sleep apnea on metabolic profile: a Population-Based Survey.

OBJECTIVE: Epidemiologic studies that control for potential confounders are needed to assess the independent associations of obstructive sleep apnea (OSA) with metabolic abnormalities. The aim of our study was to evaluate the associations of OSA with metabolic abnormalities among the adult population of Sao Paulo, Brazil. DESIGN AND METHODS: Questionnaires were applied face-to-face, full night polysomnography (PSG) was performed, and blood samples were collected in a population-based survey in Sao Paulo, Brazil, adopting a probabilistic three-stage cluster sample method. The metabolic profile included fasting glucose, insulin, and lipid levels. The hepatic insulin resistance index was assessed by the homeostasis model assessment-estimated insulin resistance (HOMAIR ). RESULTS: A total of 1,042 volunteers underwent PSG. Mild OSA and moderate to severe OSA comprised 21.2% and 16.7% of the population, respectively. Subjects with severe to moderate OSA were older, more obese, had higher fasting glucose, HOMAIR , and triglycerides (TG) levels than did the mild and non-OSA group (P < 0.001). Multivariate regression analyses showed that an apnea-hypopnea index (AHI) ≥ 15 and a time of oxy-hemoglobin saturation <90% were independently associated with impaired fasting glucose, elevated TG, and HOMAIR . CONCLUSIONS: The results of this large cross-sectional epidemiological study showed that the associations of OSA and metabolic abnormalities were independent of other risk factors.

Nocturnal blood pressure fall as predictor of diabetic nephropathy in hypertensive patients with type 2 diabetes.

BACKGROUND: Hypertensive patients with reduced blood pressure fall (BPF) at night are at higher risk of cardiovascular events (CVE). METHODS: We evaluated in hypertensive diabetic patients, if a reduced nocturnal BPF can precedes the development of diabetic nephropathy (DN). We followed 70 patients with normal urinary albumin excretion (UAE) for two years. We performed 24-hours ambulatory BP monitoring in baseline and at the end of the study. RESULTS: Fourteen (20%) patients (GI) developed DN (N = 11) and/or CVE (n = 4). Compared to the remaining 56 patients (GII) in baseline, GI had similar diurnal systolic (SBP) and diastolic BP (DBP), but higher nocturnal SBP (138 +/- 15 vs 129 +/- 16 mmHg; p < 0.05) and DBP (83 +/- 12 vs 75 +/- 11 mmHg; p < 0,05). Basal nocturnal SBP correlated with occurrence of DN and CVE (R = 0.26; P < 0.05) and with UAE at the end of the study (r = 0.3; p < 0.05). Basal BPF (%) correlated with final UAE (r = -0.31; p < 0.05). In patients who developed DN, reductions occurred in nocturnal systolic BPF (12 +/- 5 vs 3 +/- 6%, p < 0,01) and diastolic BPF (15 +/- 8 vs 4 +/- 10%, p < 0,01) while no changes were observed in diurnal SBP (153 +/- 17 vs 156 +/- 16 mmHg, NS) and DBP (91 +/- 9 vs 90 +/- 7 mmHg, NS). Patients with final UAE < 20 microg/min, had no changes in nocturnal and diurnal BP. CONCLUSIONS: Our results suggests that elevations in nocturnal BP precedes DN and increases the risk to develop CVE in hypertensive patients with T2DM.

Performance of two metabolic syndrome definitions in the estimation of cardiovascular disease among hypertensive patients.

The authors evaluated the significance of metabolic syndrome (MetS) diagnosis, as defined by the National Cholesterol Education Program (NCEP) and by the International Diabetes Federation (IDF), in the evaluation of cardiovascular risk in hypertensive patients. Among 638 patients, the prevalence of MetS was 54.7% when the IDF criteria were used, compared with 45.5% when the NCEP criteria were used. MetS correlated significantly with the presence of cardiovascular disease (CVD). In patients without type 2 diabetes mellitus (T2DM), only MetS diagnosed using the IDF criteria was associated with the presence of CVD. In those with T2DM, MetS was not associated with CVD, regardless of the criteria used. The diagnosis of MetS, using either set of criteria, was associated with the development of T2DM. We conclude that, in hypertensive patients without diabetes, a diagnosis of MetS according to IDF criteria, but not the NCEP criteria, is useful in identifying individuals with a higher probability of incident CVD. In patients with diabetes, a population already considered at high risk for CVD, a diagnosis of MetS, regardless of the criteria used, has no further impact on prognosis.

Autonomic neuropathy tests correlate with left ventricular mass and cardiac diastolic function in normotensive patients with type 2 diabetes mellitus and without left ventricular hypertrophy.

BACKGROUND: Hypertensive diabetic patients, when compared with essential hypertensive patients, have a higher left ventricular mass index (LVMI) and an impaired cardiac diastolic function (CDF). Autonomic neuropathy (AN) could contribute to this finding. OBJECTIVE: To evaluate the relationship between AN tests, and LVMI and CDF in normotensive patients with type 2 diabetes mellitus (DM2) and without AN symptoms or left ventricular hypertrophy. METHODS: In 21 normotensive patients with DM2 (group 1) and 16 control subjects (group 2), LVMI and CDF were evaluated using atrial deceleration time, isovolumic relaxation time, E wave, A wave and E/A wave ratio. AN tests performed included a deep breathing test, Valsalva manoeuvre and lying-to-standing test. RESULTS: Groups did not differ in clinical and echocardiographic characteristics. None of the patients in either group presented with left ventricular hypertrophy. In group 1, there were correlations between the deep breathing test and LVMI (r=-0.6; P<0.01) and between the deep breathing test and E/A wave ratio (r=0.4; P<0.05). No correlations were found in the control group. CONCLUSION: In DM2 patients, AN tests correlated with LVMI and CDF before left ventricular hypertrophy, hypertension, impaired CDF and diabetic AN symptoms were present. The present study suggests that AN tests could be regularly performed in DM2 patients. Any abnormalities in tests should be followed by a cardiac evaluation.

Is cystatin C a useful marker in the detection of diabetic kidney disease?

BACKGROUND/AIMS: To evaluate cystatin C as a marker of diabetic kidney disease in normoalbuminuric diabetic patients without chronic kidney disease (CKD). METHODS: A cross- sectional study was carried out comprising 243 hypertensive patients, 61 of them with type 2 diabetes, presenting normoalbuminuria and an estimated glomerular filtration rate (eGFR) >or=60 ml/min/1.73 m(2). Renal function assessment included determinations of serum creatinine and cystatin C levels, microalbuminuria, as well as eGFR through Cockcroft-Gault and Modification of Diet in Renal Disease equations. RESULTS: Diabetic patients presented higher cystatin C levels than nondiabetic patients (0.95 +/- 0.19 vs. 0.89 +/- 0.17 mg/l; p < 0.05). In the binary logistic regression, the presence of diabetes and metabolic syndrome was significantly associated with elevated cystatin C levels. Diabetic patients also presented a slightly greater albuminuria (6.72 +/- 4.43 vs. 5.07 +/- 3.59 microg/min; p < 0.05). CONCLUSIONS: Our results suggest that elevated cystatin C levels in diabetic patients may identify a certain degree of renal dysfunction even when albuminuria and eGFR do not mirror CKD. Longitudinal studies with direct GFR measures need to be done in order to confirm the value of cystatin C as an indicative of worse renal outcomes in the diabetic population.

Diuretic-induced potassium depletion and glucose intolerance are not related to hyperactivity of the renin-angiotensin-aldosterone system in hypertensive patients with the metabolic syndrome.

The metabolic syndrome (MS) has been associated with hyperactivity of the renin-angiotensin-aldosterone system (RAAS). To assess the hypothesis that diuretic therapy in MS patients through further stimulation of RAAS would elicit greater potassium (K) depletion, two groups of hypertensive patients with (MS group [MSG]; n=20) and without (control group [CG]; n=19) MS were studied. Plasma renin activity (PRA), aldosterone (PA), and K levels were determined and an oral glucose tolerance test with plasma insulin determinations for calculation of homeostasis model assessment of insulin resistance (HOMA-IR), sensitivity (ISI), and secretion (HOMA-beta) was performed, both before and 12 weeks after hydrochlorothiazide (HCT; 25 mg/d) therapy. At baseline, higher HOMA IR and HOMA-beta and lower ISI and plasma K were found in the MSG than in the CG, with no differences in PA and PRA between groups. With therapy, PRA increased similarly in both groups while PA increased only in the MSG. However, greater reduction in plasma K occurred in the CG, and the 2 groups reached similar final K values. Impairment in glucose tolerance occurred in both groups, with no change in HOMA-beta in the CG and reduction in the MSG, suggesting that diuretic therapy increases insulin resistance and impairs insulin secretion independent of abdominal obesity. These alterations could not be attributed to hyperactivity of RAAS.

Uric acid as a marker for renal dysfunction in hypertensive women on diuretic and nondiuretic therapy.

Hyperuricemia is a common finding in hypertensive patients, especially among those who are on diuretic therapy. However, its clinical relevance regarding cardiovascular and chronic kidney disease (CKD) has not clearly been established. The authors assessed whether, in a population of 385 hypertensive women categorized according to diuretic therapy, the stratification in quartiles by uric acid levels would identify a gradient of changes in renal function and in risk factors for cardiovascular disease. The following were evaluated: serum uric acid, glycemia, total and fractional cholesterol, triglycerides, apolipoprotein (Apo) B, Apo A-I, and C-reactive protein. Renal function was assessed by serum creatinine, albuminuria, and estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease equation, whereas cardiovascular risk was estimated through the Framingham score. A total of 246 women were on diuretic therapy; 139 were taking other antihypertensive medications. There was a reduction in eGFR parallel to the increase in uric acid levels, regardless of diuretic use and without a concomitant increase in albuminuria. In both groups, higher uric acid levels translated into an increase in metabolic syndrome components, in markers of insulin resistance, triglyceride / high-density lipoprotein levels, and Apo B/Apo A-I ratios, as well as in Framingham scores. Hyperuricemia was associated with an increase in inflammatory markers only in patients on diuretic therapy. In a binary logistic regression, hyperuricemia (uric acid >6.0 mg/ dL) was independently associated with CKD (eGFR <60 mL/ min / 1.73 m(2)) (odds ratio, 2.63; 95% confidence interval, 1.61-4.3; P<.001). In hypertensive women, the presence of hyperuricemia indicated a substantial degree of kidney dysfunction as well as a greater cardiovascular risk profile.

Hyperglycemia and nocturnal systolic blood pressure are associated with left ventricular hypertrophy and diastolic dysfunction in hypertensive diabetic patients.

BACKGROUND: The aim of this study was to determine if hypertensive type 2 diabetic patients, when compared to patients with essential hypertension have an increased left ventricular mass index (LVMI) and a worse diastolic function, and if this fact would be related to 24-h pressoric levels changes. METHODS: Ninety-one hypertensive patients with type 2 diabetes mellitus (DM) (group-1 [G1]), 59 essential hypertensive patients (group-2 [G2]) and 26 healthy controls (group-3 [G3]) were submitted to 24-h Ambulatory Blood Pressure Monitoring (ABPM) and echocardiography (ECHO) with Doppler. We calculated an average of fasting blood glucose (AFBG) values of G1 from the previous 4.2 years and a glycemic control index (GCI) (percentual of FBG above 200 mg/dl). RESULTS: G1 and G2 did not differ on average of diurnal systolic and diastolic BP. However, G1 presented worse diastolic function and a higher average of nocturnal systolic BP (NSBP) and LVMI (NSBP = 132 +/- 18 vs 124 +/- 14 mmHg; P < 0.05 and LVMI = 103 +/- 27 vs 89 +/- 17 g/m2; P < 0.05, respectively). In G1, LVMI correlated with NSBP (r = 0.37; P < 0.001) and GCI (r = 0.29; P < 0.05) while NSBP correlated with GCI (r = 0.27; P < 0.05) and AFBG (r = 0.30; P < 0.01). When G1 was divided in tertiles according to NSBP, the subgroup with NSBP> or =140 mmHg showed a higher risk of LVH. Diabetics with NSBP> or =140 mmHg and AFBG>165 mg/dl showed an additional risk of LVH (P < 0.05; odds ratio = 11). In multivariate regression, both GCI and NSBP were independent predictors of LVMI in G1. CONCLUSION: This study suggests that hyperglycemia and higher NSBP levels should be responsible for an increased prevalence of LVH in hypertensive patients with Type 2 DM.

A randomized, double-blind, placebo-controlled study of sibutramine in the treatment of binge-eating disorder.

BACKGROUND: Although antidepressants are the pharmacological agents most often studied in the treatment of binge-eating disorder (BED), preliminary evidence from an open trial suggests that the antiobesity agent sibutramine hydrochloride may be effective. The objective of this study was to evaluate the efficacy and tolerability of sibutramine in obese patients with BED. METHODS: After a 2-week run-in period, 60 obese outpatients (body mass index [calculated as weight in kilograms divided by the square of height in meters] 30-45), who met DSM-IV criteria for BED were randomly assigned to receive sibutramine hydrochloride (n = 30), 15 mg/d, or placebo (n = 30) in a 12-week double-blind study at 2 centers. The primary outcome measure was binge frequency, expressed as the number of days with binge-eating episodes during the past week. Secondary outcome measures included Binge Eating Scale, Beck Depression Inventory scores, weight, and treatment responder status (remission and response). For each efficacy outcome, an intent-to-treat analysis was performed using random regression methods. RESULTS: There was a significant reduction in the number of days with binge episodes in the sibutramine group compared with the placebo group (t203 = 2.14; P =.03); this was associated with an important and significant weight loss (-7.4 kg) compared with a small weight gain in the placebo group (1.4 kg) (t147 = 4.88; P<.001). Sibutramine was also associated with a significantly greater rate of reduction in Binge Eating Scale (t202 = 3.64; P<.001) and Beck Depression Inventory (t201 = 3.72; P<.001) scores. Dry mouth (P =.01) and constipation (P<.001) were more common adverse reactions with sibutramine than placebo. CONCLUSIONS: Sibutramine is effective and well tolerated in the treatment of obese patients with BED. Its effects address 3 main domains of the BED syndrome, ie, binge eating, weight, and related depressive symptoms.

Hiperandrogismo e/ou anovulaçäo crônica de causa näo definida: ênfase no papel da insulina / Hyperandrogenism and or chronic unovulation with undefined cause: enphasis in the insulin rule

Comparamos clinicamente 55 mulheres hirsutas e 45 mulheres sem manifestaçöes de excesso de hormônios androgênios, com o objetivo de avaliar diferenças clínicas na fase do desenvolvimento puberal. Para determinar se existe relaçäo entre insulinemia, nível de androgênio, ciclo menstrual e morfologia ovariana, selecionamos as primeira 27 pacientes hirsutas devido a hiperandrogenismo e/ou anovulaçäo crônica de causa näo definida (15 com ciclos regulares [grupo 1] e 12 com ciclos irregulares [grupo 2]), e realizamos dosagem dos androgênios, nível de insulina (jejum e após 2 horas da ingesta de 75g de dextrosol) e ultra-sonografia pélvica. Consideramos ovários policísticos quando havia mais de 10 cistos periféricos envoltos por estroma aumentado e ovários multicísticos quando havia mais de 10 cistos periféricos sem aumento de estroma. Observamos que as mulheres com hirsutismo tiveram desenvolvimento da menarca e pubarca mais cedo; o hirsutismo e a irregularidade menstrual surgiram na época do desenvolvimento puberal e observamos relaçao entre oligomenorréia nos primeiros ciclos e a persistência da irregularidade até na vida adulta. Considerando apenas as hirsutas com índice de massa corporal (IMC) maior do que 25, observamos que as pacientes do grupo 2 apresentaram maior nível de testoterona, LH e volume ovariano em relaçäo as pacientes do grupo 1. Observamos correlaçao entre testosterona e nsulinemia de jejum. Ovários policísticos foram mais freqëntes no grupo 2 e ovários multicísticos no grupo 1. Concluímos que as pacientes com hirsutismo com ciclos irregulares apresentam uma tendência a apresentarem maior insulinemia e ovários policísticos e as pacientes hirsutas com ciclos regulares menor insulinemia e ovários multicísticos.