Italian guidelines for the management of adult individuals with overweight and obesity and metabolic comorbidities that are resistant to behavioral treatment.

AIM: This guideline (GL) is aimed at providing a clinical practice reference for the management of adult patients with overweight or obesity associated with metabolic complications who are resistant to lifestyle modification. METHODS: Surgeons, endocrinologists, gastroenterologists, psychologists, pharmacologists, a general practitioner, a nutritionist, a nurse and a patients' representative acted as multi-disciplinary panel. This GL has been developed following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. A systematic review and network meta-analysis was performed by a methodologic group. For each question, the panel identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence. Those classified as "critical" were considered for clinical practice recommendations. Consensus on the direction (for or against) and strength (strong or conditional) of recommendations was reached through a majority vote. RESULTS: The present GL provides recommendations about the role of both pharmacological and surgical treatment for the clinical management of the adult patient population with BMI > 27 kg/m2 and < 40 kg/m2 associated with weight-related metabolic comorbidities, resistant to lifestyle changes. The panel: suggests the timely implementation of therapeutic interventions in addition to diet and physical activity; recommends the use of semaglutide 2.4 mg/week and suggests liraglutide 3 mg/day in patients with obesity or overweight also affected by diabetes or pre-diabetes; recommends semaglutide 2.4 mg/week in patients with obesity or overweight also affected by non-alcoholic fatty liver disease; recommends semaglutide 2.4 mg/week as first-line drug in patients with obesity or overweight that require a larger weight loss to reduce comorbidities; suggests the use of orlistat in patients with obesity or overweight also affected by hypertriglyceridemia that assume high-calorie and high-fat diet; suggests the use of naltrexone/bupropion combination in patients with obesity or overweight, with emotional eating; recommends surgical intervention (sleeve gastrectomy, Roux-en-Y gastric bypass, or metabolic gastric bypass/gastric bypass with single anastomosis/gastric mini bypass in patients with BMI ≥ 35 kg/m2 who are suitable for metabolic surgery; and suggests gastric banding as a possible, though less effective, surgical alternative. CONCLUSION: The present GL is directed to all physicians addressing people with obesity-working in hospitals, territorial services or private practice-and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise.

Disease control of acromegaly does not prevent excess mortality in the long term: results of a nationwide survey in Italy.

OBJECTIVE: This study aimed to assess the long-term outcome of patients with acromegaly. DESIGN: This is a multicenter, retrospective, observational study which extends the mean observation period of a previously reported cohort of Italian patients with acromegaly to 15 years of follow-up. METHODS: Only patients from the centers that provided information on the life status of at least 95% of their original cohorts were included. Life status information was collected either from clinical records or from the municipal registry offices. Standardized mortality ratios (SMRs) were computed comparing data with those of the general Italian population. RESULTS: A total of 811 patients were included. There were 153 deaths, with 90 expected and an SMR of 1.7 (95% CI 1.4-2.0, p < 0.001). Death occurred after a median of 15 (women) or 16 (men) years from the diagnosis, without gender differences. Mortality remained elevated in the patients with control of disease (SMR 1.3, 95% CI 1.1-1.6). In the multivariable analysis, only older age and high IGF1 concentrations at last available follow-up visit were predictors of mortality. The oncological causes of death outweighed the cardiovascular ones, bordering on statistical significance with respect to the general population. CONCLUSIONS: Mortality remains significantly high in patients with acromegaly, irrespectively of disease status, as long as the follow-up is sufficiently long with a low rate of patients lost to follow-up. Therapy strategy including radiotherapy does not have an impact on mortality. Oncological causes of death currently outweigh the cardiovascular causes.

Calcium/phosphate ratio: an additional tool for the clinical management of asymptomatic primary hyperparathyroidism?

PURPOSE: Serum calcium/phosphate ratio (Ca/P) has been recently proposed as an additional tool to identify primary hyperparathyroidism (PHPT), especially in patients with subclinical presentation, with a proposed cut-off of 3.3 when both values are expressed in mg/dL. No data are available on the relationship between Ca/P and the clinical presentation of PHPT. We thus evaluated this relationship in a large, single-center, unselected series. METHODS: 515 consecutive PHPT patients (mean age 65 ± 13.15 years, 77.1% females) were retrospectively evaluated at diagnosis. RESULTS: Mean Ca/P was 4.54 ± 1.5 (range 2.36-13.9), being higher than 3.3 in 88.5% of patients. Ca/P was significantly higher in (1) males, (2) symptomatic PHPT, (3) patients with 25-hydroxy vitamin D levels lower than 20 µg/L, (4) patients with osteitis fibrosa cystica, (5) patients with T score < - 2.5 at the radial site. In a multivariate regression analysis, Ca/P resulted significantly associated with PTH levels. After the exclusion of 57 patients with asymptomatic PHPT (aPHPT) patients and serum Ca higher than 1 mg/dL above the upper limit of normal range, no differences were found in Ca/P between aPHPT meeting or not surgical criteria. CONCLUSIONS: In PHPT Ca/P ratio is associated with increased biochemical and clinical severity of disease and represents a direct indicator of clinical bone damage. However, it does not seem an additional tool to identify aPHPT patients reaching surgical indication.

What factors have impact on glucocorticoid replacement in adrenal insufficiency: a real-life study.

PURPOSE: The impact of patient's characteristics on glucocorticoid (GC) replacement therapy in adrenal insufficiency (AI) is poorly evaluated. Aims of this study were to assess the influence of sex and body weight on GC dosing and to describe the choice of GC in AI of different etiologies. METHODS: We retrospectively evaluated hydrocortisone (HC) equivalent total daily dose (HC-TDD) and per-kg-daily dose (HC-KDD) in 203 patients (104 primary AI [pAI], 99 secondary AI [sAI]) followed up for ≥ 12 months. They were treated with HC, modified-release HC (MRHC) or cortisone acetate (CA) and fludrocortisone acetate (FCA) in pAI. RESULTS: At baseline, CA was preferred both in pAI and sAI; at last visit, MRHC was most used in pAI (49%) and CA in sAI (73.7%). Comparing the last visit with baseline, in pAI, HC-TDD and HC-KDD were significantly lower (p = 0.04 and p = 0.006, respectively), while FCA doses increased during follow-up (p = 0.02). The reduction of HC-TDD and HC-KDD was particularly relevant for pAI women (p = 0.04 and p = 0.002, respectively). In sAI patients, no change of HC-KDD and HC-TDD was observed, and we found a correlation between weight and HC-TDD in males (r 0.35, p = 0.02). CONCLUSIONS: Our real-life study demonstrated the influence of etiology of AI on the type of GC used, a weight-based tailoring in sAI, a likely overdosage of GC treatment in pAI women at the start of treatment and the possibility to successfully increase FCA avoiding GC over-treatment. These observations could inform the usual clinical practice.

Clinical presentation and management of patients with primary hyperparathyroidism in Italy.

PURPOSE: Evaluation of the phenotype of primary hyperparathyroidism (PHPT), adherence to International Guidelines for parathyroidectomy (PTx), and rate of surgical cure. METHOD: From January 2014-January 2016, we performed a prospective, multicenter study in patients with newly diagnosed PHPT. Biochemical and instrumental data were collected at baseline and during 1-year follow-up. RESULTS: Over the first year we enrolled 604 patients (age 61 ± 14 years), mostly women (83%), referred for further evaluation and treatment advice. Five hundred sixty-six patients had sporadic PHPT (93.7%, age 63 ± 13  years), the remaining 38 (6.3%, age 41 ± 17  years) had familial PHPT. The majority of patients (59%) were asymptomatic. Surgery was advised in 281 (46.5%). Follow-up data were available in 345 patients. Eighty-seven of 158 (55.1%) symptomatic patients underwent PTx. Sixty-five (53.7%) of 121 asymptomatic patients with at least one criterion for surgery underwent PTx and 56 (46.3%) were followed without surgery. Negative parathyroid imaging studies predicted a conservative approach [symptomatic PHPT: OR 18.0 (95% CI 4.2-81.0) P < 0.001; asymptomatic PHPT: OR 10.8, (95% CI 3.1-37.15) P < 0.001). PTx was also performed in 16 of 66 (25.7%) asymptomatic patients without surgical criteria. Young age, serum calcium concentration, 24 h urinary calcium, positive parathyroid imaging (either ultrasound or MIBI scan positive in 75% vs. 16.7%, P = 0.001) were predictors of parathyroid surgery. Almost all (94%) of patients were cured by PTx. CONCLUSIONS: Italian endocrinologists do not follow guidelines for the management of PHPT. Negative parathyroid imaging studies are strong predictors of a non-surgical approach. PTx is successful in almost all patients.

The basal to total insulin ratio in outpatients with diabetes on basal-bolus regimen.

OBJECTIVE: To evaluate the basal/total ratio of daily insulin dose (b/T) in outpatients with diabetes type 1 (DM1) and type 2 (DM2) on basal-bolus regimen, by investigating whether there is a relationship with HbA1c and episodes of hypoglycemia. METHODS: Multicentric, observational, cross-sectional study in Italy. Adult DM1 (n = 476) and DM2 (n = 541) outpatients, with eGFR >30 mL/min/1.73 m2, on a basal-bolus regimen for at least six months, were recruited from 31 Italian Diabetes services between March and September 2016. Clinicaltrials.govID: NCT03489031. RESULTS: Total daily insulin dose was significantly higher in DM2 patients (52.3 ± 22.5 vs. 46 ± 20.9 U/day), but this difference disappeared when insulin doses were normalized for body weight. The b/T ratio was lower than 0.50 in both groups: 0.46 ± 0.14 in DM1 and 0.43 ± 0.15 in DM2 patients (p = 0.0011). The b/T was significantly higher in the patients taking metformin in both groups, and significantly different according to the type of basal insulin (Degludec, 0.48 in DM1 and 0.44 in DM2; Glargine, 0.44 in DM1 and 0.43 in DM2; Detemir, 0.45 in DM1 and 0.39 in DM2). The b/T ratio was not correlated in either group to HbA1c or incidence of hypoglycemia (<40 mg/dL, or requiring caregiver intervention, in the last three months). In the multivariate analysis, metformin use and age were independent predictors of the b/T ratio in both DM1 and DM2 patients, while the type of basal insulin was an independent predictor only in DM1. CONCLUSION: The b/T ratio was independent of glycemic control and incidence of hypoglycemia.

Correction to: The basal to total insulin ratio in outpatients with diabetes on basal-bolus regimen.

[This corrects the article DOI: 10.1007/s40200-018-0358-2.].

Mild primary hyperparathyroidism as defined in the Italian Society of Endocrinology's Consensus Statement: prevalence and clinical features.

BACKGROUND: Mild primary hyperparathyroidism (PHPT) was recently clearly defined for the first time. Our study was thus aimed to pinpoint proportion and clinical characteristics of this kind of patients. DESIGN AND PATIENTS: We retrospectively evaluated our series of 360 consecutive patients with PHPT, selecting those with all features allowing a correct classification (serum total and ionized calcium, phosphate, creatinine, PTH, 25OHD, urinary calcium, renal and neck ultrasound, MIBI scintiscan, and DEXA at lumbar spine, femoral neck, and distal third of radius). Patients were defined asymptomatic (aPHPT) when bone or kidney was not involved and no hypercalcemic symptom occurred; mild PHPT was defined as aPHPT not meeting updated surgical criteria. RESULTS: Seventy-five patients among 172 classified as aPHPT had all available data required for surgical evaluation and could be evaluated. Sixty/75 met surgical criteria and the remaining 15 were classified as mild. Mild PHPT patients had lower total and ionized calcium, urinary calcium, and PTH levels than aPHPT meeting surgical criteria, while vitamin D levels and BMD were similar. CONCLUSIONS: Mild PHPT strictly defined according to the last consensus represents a small subgroup with a less active form of the disease.

Primary hyperparathyroidism and Klinefelter's syndrome in a young man.

UNLABELLED: We report the association of primary hyperparathyroidism (PHPT) and Klinefelter's syndrome (KS) in a 22-year-old male complaining of worsening fatigue. PHPT was asymptomatic at the diagnosis, but the patient had worsening hypercalcemia and osteoporosis, and developed acute renal colic. He then underwent parathyroidectomy with resection of a single adenoma and normalization of calcium and parathyroid hormone levels. Clinical and therapeutic implications of this rare association are discussed. LEARNING POINTS: The coexistence of KS and PHPT is very uncommon.Patients with mild PHPT often have nonspecific symptoms that may be confused and superimposed with those of hypogonadism.KS patients, especially when young and already osteoporotic at diagnosis, should be screened for other causes of secondary osteoporosis, in particular PHPT.

Predictors of morbidity and mortality in acromegaly: an Italian survey.

OBJECTIVE: To describe demographic and hormonal characteristics, comorbidities (diabetes mellitus and hypertension), therapeutic procedures and their effectiveness, as well as predictors of morbidity and mortality in a nationwide survey of Italian acromegalic patients. DESIGN: Retrospective multicenter epidemiological study endorsed by the Italian Society of Endocrinology and performed in 24 tertiary referral Italian centers. The mean follow-up time was 120 months. RESULTS: A total of 1512 patients, 41% male, mean age: 45±13 years, mean GH: 31±37 µg/l, IGF1: 744±318 ng/ml, were included. Diabetes mellitus was reported in 16% of cases and hypertension in 33%. Older age and higher IGF1 levels at diagnosis were significant predictors of diabetes and hypertension. At the last follow-up, 65% of patients had a controlled disease, of whom 55% were off medical therapy. Observed deaths were 61, with a standardized mortality ratio of 1.13 95% (confidence interval (CI): 0.87-1.46). Mortality was significantly higher in the patients with persistently active disease (1.93; 95% CI: 1.34-2.70). Main causes of death were vascular diseases and malignancies with similar prevalence. A multivariate analysis showed that older age, higher GH at the last follow-up, higher IGF1 levels at diagnosis, malignancy, and radiotherapy were independent predictors of mortality. CONCLUSIONS: Pretreatment IGF1 levels are important predictors of morbidity and mortality in acromegaly. The full hormonal control of the disease, nowadays reached in the majority of patients with modern management, reduces greatly the disease-related mortality.

Prevalence and characteristics of metabolic syndrome in primary hyperparathyroidism.

AIMS: Primary hyperparathyroidism (pHPT) is characterized by an increased frequency of glucose tolerance abnormalities associated with insulin resistance. Few studies evaluated the prevalence of metabolic syndrome (MetS) in pHPT and whether there are differences between asymptomatic pHPT patients and symptomatic ones. Thus, we sought to investigate the prevalence of MetS in pHPT patients in comparison to the prevalence of MetS in Italian population. SUBJECTS AND METHODS: We conducted a retrospective chart review of 294 pHPT patients, of these 154 [age (mean ± SD) 58.7 ± 13.3 yr, body mass index 25.6 ± 4.8 kg/m(2); serum calcium (11.3 ± 1.2 mg/dl) 2.8 ± 0.3 mmol/l; PTH 234.8 ± 224.3 ng/l] met the inclusion criteria. A modified National Cholesterol Educational Program (NCEP)/Adult Treatment Panel III (ATP III) definition of the MetS was used. Prevalence of MetS was compared with that reported for the Italian population (Progetto Cuore Study). RESULTS: The prevalence of the MetS (34/154, 22.1%) was similar to that reported in the general Italian population. Asymptomatic pHPT patients were older (62.1 ± 12.7 vs 56.4 ± 13.2 yr, p<0.008) and showed higher prevalence of MetS than symptomatic ones (30.2% vs 16.5%, p<0.045). Moreover the prevalence of nephrolitiasis or overt bone disease was not different between patients MetS+pHPT compared to MetS-pHPT, whereas femoral bone mineral density (BMD) was higher in MetS+pHPT (p<0.003). In the logistic regression model age and femoral BMD were independent predictors of MetS. CONCLUSIONS: The prevalence of MetS in pHPT is not increased in comparison to the general population, thus, its diagnosis is not an appropriate tool to identify the additional cardiovascular risk related to pHPT. Difference in age affects the increased prevalence of MetS in asymptomatic pHPT patients.

AME position statement on adrenal incidentaloma.

OBJECTIVE: To assess currently available evidence on adrenal incidentaloma and provide recommendations for clinical practice. DESIGN: A panel of experts (appointed by the Italian Association of Clinical Endocrinologists (AME)) appraised the methodological quality of the relevant studies, summarized their results, and discussed the evidence reports to find consensus. RADIOLOGICAL ASSESSMENT: Unenhanced computed tomography (CT) is recommended as the initial test with the use of an attenuation value of ≤10 Hounsfield units (HU) to differentiate between adenomas and non-adenomas. For tumors with a higher baseline attenuation value, we suggest considering delayed contrast-enhanced CT studies. Positron emission tomography (PET) or PET/CT should be considered when CT is inconclusive, whereas fine needle aspiration biopsy may be used only in selected cases suspicious of metastases (after biochemical exclusion of pheochromocytoma). HORMONAL ASSESSMENT: Pheochromocytoma and excessive overt cortisol should be ruled out in all patients, whereas primary aldosteronism has to be considered in hypertensive and/or hypokalemic patients. The 1 mg overnight dexamethasone suppression test is the test recommended for screening of subclinical Cushing's syndrome (SCS) with a threshold at 138 nmol/l for considering this condition. A value of 50 nmol/l virtually excludes SCS with an area of uncertainty between 50 and 138 nmol/l. MANAGEMENT: Surgery is recommended for masses with suspicious radiological aspects and masses causing overt catecholamine or steroid excess. Data are insufficient to make firm recommendations for or against surgery in patients with SCS. However, adrenalectomy may be considered when an adequate medical therapy does not reach the treatment goals of associated diseases potentially linked to hypercortisolism.

Interplay between serum osteocalcin and insulin sensitivity in primary hyperparathyroidism.

Osteocalcin (OC) has been proposed as a regulator of insulin sensitivity in both humans and other animals. Primary hyperparathyroidism (PHPT) is characterized by high OC levels and insulin resistance. The aim of this study was to evaluate whether in PHPT the link between OC levels and blood markers of insulin resistance was maintained. In a consecutive series of 219 adult PHPT patients, serum OC as well as fasting insulin and glucose levels were measured. Insulin sensitivity was estimated by homeostatic model assessment (HOMA2-S%). The same parameters were evaluated in a subgroup of 45 patients after parathyroidectomy (PTX). PHPT patients were characterized by markedly high OC levels. After subdividing them according to glucose tolerance, it was found that OC was similar in subjects with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT), while diabetic subjects had lower serum OC than those with NGT (P < 0.02) or IGT (P < 0.04). OC was negatively associated with fasting glucose and positively associated with HOMA2-S%. OC independently predicted HOMA2-S% in a multivariate analysis. In the subgroup of surgically cured PHPT patients, OC levels significantly decreased after PTX, while HOMA2-S% did not change. Our findings indicate that in PHPT there is a positive relationship between OC and glucose metabolism, OC being one of the predictors of insulin sensitivity. However, data in surgically cured patients, showing OC normalization in spite of unchanged HOMA2-S%, suggest that OC does not likely play a major role in affecting insulin sensitivity in PHPT.

Insulin resistance is not coupled with defective insulin secretion in primary hyperparathyroidism.

AIMS: An increased frequency of both impaired glucose tolerance and Type 2 diabetes mellitus (DM) has been reported in primary hyperparathyroidism (pHPT), thus we sought to investigate insulin sensitivity and insulin secretion in a large series of pHPT patients. SUBJECTS AND METHODS: One hundred and twenty-two consecutive pHPT patients without known DM were investigated [age (mean +/- sd) 59.3 +/- 13.6 years, body mass index (BMI) 25.7 +/- 4.2 kg/m(2); serum calcium 2.8 +/- 0.25 mmol/l; PTH 203.2 +/- 145.4 ng/l]. Sixty-one control subjects were matched, according to the degree of glucose tolerance, in a 2 : 1 patient:control ratio. Fasting- and oral glucose tolerance test-derived estimates of insulin sensitivity and secretion were determined by means of the quantitative insulin sensitivity check index (QUICKI) and the insulin sensitivity index (ISI) composite. RESULTS: Both the QUICKI and ISI composite were lower in pHPT patients than control subjects (P < 0.03 and P < 0.05, respectively) after adjusting for age, systolic blood pressure and BMI. Conversely, all insulin secretion estimates were significantly increased in pHPT patients than in control subjects (P < 0.04 and P < 0.03, respectively) and after adjusting for age, systolic blood pressure and BMI. Log serum calcium levels were negatively associated with the QUICKI and log ISI composite (R = -0.30, P = 0.001; R = -0.23, P = 0.020, respectively) in pHPT patients. Serum calcium levels significantly and independently contributed to impaired insulin sensitivity in multivariate analysis (QUICKI as dependent variable: beta = -0.31, P = 0.004, R(2) = 0.15; log ISI composite as dependent variable: beta = -0.29, P = 0.005, R(2) = 0.16). CONCLUSIONS: Our study confirms a reduction in both basal and stimulated insulin sensitivity in primary hyperparathyroidism, in spite of increased insulin secretion. Moreover, our data show for the first time a significant relationship between hypercalcaemia and insulin sensitivity in this condition.

Glomerular filtration rate and parathyroid hormone secretion in primary hyperparathyroidism.

CONTEXT: The recent Third International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism (PHPT) set 60 ml/min as the precise level of glomerular filtration rate (GFR) below which surgery is recommended because it is considered a threshold of concern in patients with PHPT. OBJECTIVE: The aim of the study was to investigate the relationship between different stages of renal insufficiency and PTH levels in PHPT patients. DESIGN: We conducted a cross-sectional study. PATIENTS AND METHODS: We studied 294 consecutive PHPT patients. Biochemical evaluation included total and ionized serum calcium, phosphate, creatinine, immunoreactive intact PTH, and 25-hydroxyvitamin D3 levels in the fasting state. GFR was assessed with the Modification of Diet in Renal Disease Study formula. RESULTS: The mean GFR of the whole group of PHPT patients was 92.3 +/- 31.6 ml/min x 1.73 m(2). The patients were divided into four groups according to National Kidney Foundation Disease Outcomes Quality Initiative (K/DOQI) guidelines: group 1 with normal or increased GRF (>90 ml/min x 1.73 m(2); n = 153); group 2 with mild decreased GFR (60-89 ml/min x 1.73 m(2); n = 90); group 3 with moderately decreased GFR (30-59 ml/min x 1.73 m(2); n = 45); and group 4 with severely decreased GFR (<30 ml/min x 1.73 m(2); n = 6). PTH levels were comparable across groups 1-3, whereas group 4 showed significantly higher PTH levels (P < 0.0001). CONCLUSION: In our series of PHPT patients, only a severe impairment of GFR was characterized by a further PTH increase. These findings challenge the concept of a PTH elevation below the threshold of 60 ml/min of GFR.

B-type natriuretic peptide levels and insulin resistance in patients with severe ischemic myocardial dysfunction.

B-type natriuretic peptide (BNP) is an important clinical parameter of severity in congestive heart failure (CHF). Recent findings suggest a close relation between lipid and glucose metabolism and the natriuretic peptide axis, even if conflicting data exist on the relationship between natriuretic peptide levels and insulin resistance (IR). Thus, we sought to investigate potential relations between BNP level and IR in 134 patients with severe ischemic myocardial dysfunction [mean+/-SD: age =64.8+/-9.6 yr, male/female =104/30; body mass index (BMI) =25.5+/-4.05 kg/m2, 26.1% diabetics; ejection fraction (EF) = 30.2+/-7.7%]. In univariate analysis, an inverse relationship between BNP levels and EF% was observed (R=-0.43, p=0.0006). Moreover, we found an inverse association between BNP levels and BMI (R=-0.27, p=0.036), and also between BNP and homeostasis model assessment of insulin resistance (HOMA-IR) (R=-0.27, p=0.039). In multivariate analysis, EF% and HOMA-IR were significantly and independently associated with logarithmically transformed BNP levels (beta=-0.40, p=0.019 and beta=-0.26, p=0.042, respectively; R2=0.36). In conclusion, in patients with severe ischemic myocardial dysfunction EF and IR are independently associated with BNP levels explaining about 1/3 of the variability of this parameter. Multiple potential mechanisms may underlie this association, but it seems now clinically important to take into account also metabolic features when interpreting plasma natriuretic peptide concentrations obtained for diagnostic or prognostic purposes.

Effects of extra virgin olive oil supplementation at two different low doses on lipid profile in mild hypercholesterolemic subjects: a randomised clinical trial.

Olive oil, the principal fat of Mediterranean Diet, is known to improve several cardiovascular risk factors at relatively high doses together with intensive modifications of dietary habits. Since this is hard to obtain in the long term, an intervention with encapsulated oil supplements might be more feasible. Aim of this preliminary study was to investigate the effects of the supplementation of a moderate amount of encapsulated extra virgin olive oil vs a lower dose in mildly hypercholesterolemic subjects, as part of their established diet, on blood lipid profile. A prospective randomized study was performed. Thirty-four mildly hypercholesterolemic subjects [age, mean+/-SD: 46+/-7 yr; total cholesterol (TC): 235+/-28 mg/dl] were randomly assigned to receive 2 g (group A) or 4 g (group B) per os of extra-virgin olive oil for 3 months. TC, triglycerides (TG), LDL cholesterol, HDL cholesterol, apolipoprotein A1 (Apo-AI), apolipoprotein B (Apo-B), and atherogenic index of plasma (AIP) were evaluated at the beginning and at the end of the study. In group B, but not in group A, a significant reduction of Apo-B values (7%) was observed; TG concentrations showed a trend towards reduction and Apo-A1 values a trend towards increase (9%). A significant decrease in Apo-B/Apo-A1 ratio (p<0.01) was also observed in group B. Extra virgin olive oil supplementation significantly decreased AIP from baseline in group B (p<0.05). The results of the present study seem to suggest that the daily supplementation, on top of the normal diet, of at least 4 g of extra virgin olive oil, in mildly hypercholesterolemic subjects, is associated to favorable modifications of the plasmatic lipid profile.