Testosterone supplementation and bone parameters: a systematic review and meta-analysis study.

BACKGROUND: The role of testosterone (T) replacement therapy (TRT) in subjects with late onset hypogonadism is still the object of an intense debate. METHODS: All observational studies and placebo-controlled or -uncontrolled randomized trials (RCTs) comparing the effect of TRT on different bone parameters were considered. RESULTS: Out of 349 articles, 36 were considered, including 3103 individuals with a mean trial duration of 66.6 weeks. TRT improves areal bone mineral density (aBMD) at the spine and femoral neck levels in observational studies, whereas placebo-controlled RTCs showed a positive effect of TRT only at lumber spine and when trials included only hypogonadal patients at baseline (total testosterone < 12 nM). The effects on aBMD were more evident in subjects with lower T levels at baseline and increased as a function of trial duration and a higher prevalence of diabetic subjects. Either T or estradiol increase at endpoint contributed to aBMD improvement. TRT was associated with a significant reduction of bone resorption markers in observational but not in controlled studies. CONCLUSION: TRT is able to inhibit bone resorption and increase bone mass, particularly at the lumbar spine level and when the duration is long enough to allow the anabolic effect of T and estrogens on bone metabolism to take place.

Eating psychopathology in ballet dancers: a meta-analysis of observational studies.

OBJECTIVE: To assess whether ballet dancers have higher eating psychopathology mean scores than the general population. METHODS: Meta-analysis of cross-sectional observational studies comparing the scores of one or more of the validated eating psychopathological scales between ballet dancers and any control groups. RESULTS: Twelve studies were included in the metanalysis. Ballet dancers had a significantly higher EAT score (12 studies retrieved, SMD 0.82 [95% CI 0.44-1.19], p < 0.00001, I2 = 84)]; subgroup analysis suggested a possible role of control subjects' choice in explaining heterogeneity. Scores on the EDI subscales of Drive for Thinness, Bulimia, and Body dissatisfaction were available from four studies; Drive for Thinness was higher in ballet dancers (SMD 0.62 [0.01, 1.22]), as well as the Bulimia scale (SMD 0.38 [0.02, 0.73], p = 0.04) and the Body Dissatisfaction scale (SMD 0.34 [0.15, 0.53]). Data on Perfectionism, Interpersonal problems, Ineffectiveness, and Maturity fears, were available from three studies. Higher scores in Perfectionism (SMD 0.68 [0.24, 1.12] p = 0.02), Interpersonal problems (SMD 0.24 [0.02, 0.47], in Inefficacy, (SMD 2.18 [1.31, 3.06]) were found for ballet dancers; on the other hand, Maturity fears scores were not significantly different between ballet dancers and controls (IV-MD = 0.15 [- 0.07, 0.36]). Seven studies reported tests not performed elsewhere. DISCUSSION: Ballet dancers show a higher level of restriction and drive for thinness than controls, and they may be, therefore, at higher risk for the development of eating disorders. Available studies do not allow the discrimination of dysfunctional eating attitudes and behaviors from adaptive responses. LEVEL OF EVIDENCE: Level I (evidence obtained from systematic reviews and meta-analyses).

COVID-19 Vaccine Hesitancy and Early Adverse Events Reported in a Cohort of 7,881 Italian Physicians.

Background: The COVID-19 vaccination campaign began in Italy at the end of December 2020, with the primary aim of immunizing healthcare professionals, using the EMA approved mRNA vaccines (Comirnaty® by Pfizer/BioNTech; mRNA-1273 by Moderna) and recombinant adenoviral vaccine (Vaxzevria® by AstraZeneca). The study aimed at evaluating the prevalence and motivations underlying Vaccine Hesitancy, as well as the incidence and type of adverse events associated with COVID-19 vaccination. Methods: Cross-sectional study. Data were collected January 1st to 28th 2021 using a purposely created online self-administered questionnaire from a selected cohort of Italian physicians. Results: Overall, 7,881 questionnaires were analyzed: 6,612 physicians had received one dose, and 1,670 two doses of Comirnaty®; 30 had received one dose of mRNA-1273. Vaccine Hesitancy rate was 3.6%; it correlated with prior SARS-CoV-2 infection, diabetes, Adverse Eventss at previous vaccinations and refusal of 2020 flu vaccine, and was mainly motivated by concerns about vaccine Adverse Events. Typical Adverse Events were pain/itching/paresthesia at the inoculation site, followed by headache, fever, fatigue and myalgia/arthralgia occurring more frequently after the second dose (77.8 vs 66.9%; p<0.001), and in subjects with a prior SARS-CoV-2 infection. Conclusion: Adherence to COVID-19 vaccination is high among physicians. Adverse Events are typically mild and more frequent in people with a prior SARS-CoV-2 infection.

Trust of Italian healthcare professionals in COVID-19 (anti-SARS-COV-2) vaccination.

ABSTRACT: Background. Vaccination is one of the most effective tools available to Public Health. Its potential usefulness is threatened by the rise of vaccine hesitancy among the general population, which has grown as much as to prompt the World Health Organization to express its concerns on the matter. The risk posed by vaccine hesitancy is even more concerning in the light of the efforts to curb the ongoing COVID-19 pandemic, which focus mainly on mass vaccination campaigns. This holds especially true when applied to healthcare professionals, among whom vaccine hesitancy can be particularly detrimental. For these reasons, our study focuses on potential determinants of vaccine hesitancy among healthcare professionals. Study design. The study is a cross-sectional study. Methods. Data were collected from January 1st to February 16th, by means of a self-administered online questionnaire in a cohort of Italian healthcare professionals. Results. Overall, 10,898 questionnaires were collected. Among the respondents, 1.1% expressed vaccine hesitancy. Hesitancy was less frequent in professionals involved in Primary Care and in the Clinical Scien-ces/Public Health group. Among clinicians, paediatricians, oncologists, and geriatrists showed especially accepting attitudes towards vaccination. Lower hesitancy rates were also registered among the respondents who already had received influenza vaccination and who never had any adverse effects following vaccination. Higher hesitancy rates were observed among individuals who had family members aged >65 years and with a history of severe adverse reactions to vaccination. Conclusion. Vaccine hesitancy rates were extremely low among participants in our study. Some medical specialties shown were particularly accepting towards vaccination. The potential predictors and protective factors pointed out by our analysis might allow more refined targets.

Dypeptidylpeptidase-4 inhibitors and the cardiovascular system: How to manage the fil rouge.

Dypeptidylpeptidase-4 (DPP-4) inhibitors are a therapeutic option for improving glucose control in patients with type 2 diabetes. They can be prescribed at different stages of the natural history of the disease because of their low risk for hypoglycemia and associated weight gain. For all new drugs for diabetes, the US Food and Drug Administration requires the demonstration of the cardiovascular (CV) safety profile through pooled analyses of phase 3 studies or specifically designed trials. A significant superiority over placebo has been observed with a sodium-dependent glucose transporter-2 inhibitor, empagliflozin, and two glucagon-like peptide-1 receptor agonists, liraglutide and semaglutide, thus suggesting cardioprotective effects for some antidiabetic drugs. The neutral results of CV safety trials on DPP-4 inhibitors have been disappointing, appearing to contradict the data from pooled analyses and meta-analyses of early trials. The main aim of this review is to find a possible interpretation for the differences between the results of these early trials and the CV safety studies with DPP-4 inhibitors. We conclude that the hypothesis of additional beneficial effects by DPP-4 inhibitors (beyond the improvement of glucose control), on the CV system in low-risk patients in primary prevention, needs to be verified with specifically designed studies.

Effects of PCSK9 inhibitors on LDL cholesterol, cardiovascular morbidity and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors determine a wide reduction of LDL cholesterol, greater than other lipid-lowering agents. The present meta-analysis is aimed at the assessment of PCSK9 inhibitors effect on LDL Cholesterol, cardiovascular morbidity and all-cause mortality. METHODS AND RESULTS: A Medline and Clinicaltrials.gov search for eligible studies until December 1, 2017, was performed. All randomized trials (> 12 weeks) comparing PCSK-9 inhibitors with placebo or active drugs were retrieved. Primary endpoints: (a) LDL cholesterol at endpoint; (b) Major cardiovascular events (MACE); (c) All-cause mortality. Data extraction was performed independently by two of the authors, and conflicts resolved by a third investigator. A total of 38 trials fulfilling the inclusion criteria were identified, with mean duration of 36.4 weeks. The reduction of LDL cholesterol at endpoint, versus placebo, ezetimibe, and high-dose statins was - 65.3 [- 69.6, - 60.9]%, - 57.7 [- 68.3;- 47.0]%, and - 34.5 [- 40.8;- 28.1]%, respectively, with alirocumab possibly showing a smaller effect than the other drugs of the class. Treatment with PCSK9 inhibitors was associated with a reduction in the incidence of MACE (Mantel-Haenszel Odds Ratio [MH-OR] 0.83 [0.78, 0.88]), with significant effects of alirocumab and evolocumab only. The number needed to treat for 2 years for preventing one event was 89. All-cause mortality and cardiovascular mortality were not reduced by treatment with PCSK-9 inhibitors (MH-OR 0.94 [0.84, 1.04] and 0.97[0.86;1.09]). CONCLUSIONS: PCSK-9 inhibitors are effective in reducing LDL cholesterol and the incidence of major cardiovascular events in high-risk patients. Bococizumab does not show significant effects on MACE. REGISTRATION NUMBER: PROSPERO-CRD42018087640.

Adjustment of insulin doses when switching from glargine 100 U/ml or detemir to degludec: an observational study.

BACKGROUND: Degludec is a long-acting insulin with a longer duration of action and a greater day-to-day reproducibility of absorption in comparison with previous long-acting insulin formulations. The aim is the definition of the change in insulin needs in patients switching from detemir/glargine to degludec in real-life conditions. METHODS: In this retrospective cohort observational study, all outpatients with either type 1 or type 2 diabetes, starting therapy with degludec insulin-after a prior treatment with either detemir or glargine insulin for at least 6 months-were included. RESULTS: The analysis was performed on 266 patients, 172 and 96 with type 1 and type 2 diabetes, respectively. The equations describing the relationship between baseline and follow-up doses of basal insulin (6 months) were Y = 3.39 + 0.78X and Y = 0.44 + 0.69X, in patients receiving detemir/glargine either once or twice daily, respectively (Y = degludec dose at 6 months and X = basal insulin dose at switch). The corresponding equations for prandial insulin doses were y = 1.83 + 0.83*x and y = 2.85 + 0.80*x for those on pre-switch once or twice-daily basal insulin, respectively. In type 2 diabetes, the switch was associated with a reduction of basal insulin doses only in those with a prior twice-daily treatment with basal insulin. The reduction of prandial insulin reached statistical significance only in patients previously treated with basal insulin once daily. CONCLUSIONS: The present results provide a suggestion for a simple method for the adjustment of basal and prandial insulin doses in type 1 diabetic patients, switching from glargine or detemir to degludec.

Clinical impact of the new SIAPEC-IAP classification on the indeterminate category of thyroid nodules.

BACKGROUND: The increasing frequency in the diagnosis of thyroid nodules has raised a growing interest in the search for new diagnostic tools to better select patients deserving surgery. In 2014, the major Italian Societies involved in the field drafted a new cytological classification, to better stratify pre-surgical risk of thyroid cancer, especially for the indeterminate category, split into TIR3A and TIR3B subclasses, associated to different therapeutic decisions. MATERIALS AND METHODS: This retrospective cross-sectional survey analyzed thyroid fine-needle aspiration biopsy performed at our outpatient clinic before and after the introduction of the new SIAPEC-IAP consensus in May 2014. RESULTS: 8956 thyroid nodules were included in the analysis: 5692 were evaluated according to the old classification and 3264 according to the new one. The new criteria caused the overall prevalence of TIR3 to increase from 6.1 to 20.1%. Of those, 10.7 and 9.4% were included in the TIR3A and TIR3B subgroups, respectively. Each of the 213 TIR3B nodules underwent surgery and 86 (40.4%) were diagnosed as thyroid cancer, while among the 349 TIR3A nodules, only 15 of the 60 that underwent surgery were found to be thyroid cancer. CONCLUSIONS: This analysis shows that the new SIAPEC-IAC criteria significantly increased the proportion of the overall TIR3 diagnosis. The division of TIR3 nodules into two subgroups (A and B) allowed a better evaluation of the oncologic risk and a better selection of patients to be referred to surgery.

Dietary intake and major food sources of polyphenols in people with type 2 diabetes: The TOSCA.IT Study.

PURPOSE: Proper evaluation of polyphenols intake at the population level is a necessary step in order to establish possible associations with health outcomes. Available data are limited, and so far no study has been performed in people with diabetes. The aim of this work was to document the intake of polyphenols and their major food sources in a cohort of people with type 2 diabetes and in socio-demographic subgroups. METHODS: We studied 2573 men and women aged 50-75 years. Among others, anthropometry was measured by standard protocol and dietary habits were investigated by food frequency questionnaire (EPIC). The intake of polyphenols was evaluated using US Department of Agriculture and Phenol-Explorer databases. RESULTS: The mean total polyphenol intake was 683.3 ± 5.8 mg/day. Non-alcoholic beverages represented the main food source of dietary polyphenols and provided 35.5% of total polyphenol intake, followed by fruits (23.0%), alcoholic beverages (14.0%), vegetables (12.4%), cereal products and tubers (4.6%), legumes (3.7%) and oils (2.1%); chocolate, cakes and nuts are negligible sources of polyphenols in this cohort. The two most important polyphenol classes contributing to the total intake were flavonoids (47.5%) and phenolic acids (47.4%). Polyphenol intake increased with age and education level and decreased with BMI; furthermore, in the northern regions of Italy, the polyphenol intake was slightly, but significantly higher than in the central or southern regions. CONCLUSIONS: The study documents for the first time the intake of polyphenols and their main food sources in people with diabetes using validated and complete databases of the polyphenol content of food. Compared with published data, collected in people without diabetes, these results suggest a lower intake and a different pattern of intake in people with diabetes.

Attending Diabetes Clinics is associated with a lower all-cause mortality. A meta-analysis of observational studies performed in Italy.

OBJECTIVE: The epidemiological explosion of diabetes is a challenge for Health Systems and the identification of the most appropriate models of care are warranted. The inclusion of primary care physicians in the models is unquestioned whereas the role played by secondary and tertiary care (Diabetes Clinic) is often debated. However, studies focusing on hard endpoints and comparing Diabetes Clinic attendance vs. no attendance are scant. RESEARCH DESIGN AND METHODS: A meta-analysis was performed including all observational cohort studies performed in Italy, reporting crude and/or adjusted estimates of all-cause mortality in patients with diabetes attending or not attending Diabetes Clinics. Attendance was defined by prescriptions and reimbursement of specialist visits by the National Health System. RESULTS: Three studies enrolling 191,847 subjects with diabetes were included in the analysis, and about half of them had at least one visit in the Diabetes Clinic per year. During the follow-up, ranging 1-11 years, 9653 subjects died. Mortality was remarkably lower in subjects attending Diabetes Clinic (MH-OR 0.70, 95% CI 0.55-0.88, p = 0.002). Results were confirmed after adjusting for confounders (MH-OR 0.81, 95% CI 0.69-0.95, p = 0.009). CONCLUSIONS: The results of the present study suggest that attending Diabetes Clinics is associated with a lower all-cause mortality. This finding might be instrumental to implement the best models of care for persons with diabetes.

Glucagon-like peptide-1 receptor agonists and atrial fibrillation: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: The pharmacological stimulation of GLP-1 receptors is associated with an increase in heart rate. A pooled analysis of patient-level data from phase III trials with albiglutide revealed a significant increase in the risk of atrial fibrillation. Aim of the present meta-analysis is to summarize all available evidence on the effects of individual GLP-1 receptor agonists (RA), and of the whole class, on the incidence of atrial fibrillation. METHODS: A Medline search for GLP-1 RA (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, or semaglutide) was performed, collecting all randomized clinical trials with a duration ≥12 weeks, enrolling patients with type 2 diabetes and comparing a GLP-1 RA with placebo or any other non-GLP-1 RA drug. RESULTS: Of the 113 trials fulfilling the inclusion criteria, 19 did not report information on atrial fibrillation, whereas 63 reported zero events in all treatment groups. In the remaining trials (enrolling 17,966 and 15,305 patients in GLP-1 RA and comparator arms, respectively, 55.3% women, with a mean age of 57.0 ± 3.8 years), treatment with GLP-1 RA was not associated with a significant increase in the incidence of atrial fibrillation [Mantel-Haenszel OR (95% CI) 0.87 (0.71-1.05), p = 0.15]. CONCLUSIONS: In conclusion, available data suggest that GLP-1 RA is not associated with atrial fibrillation, with the only possible exception of albiglutide. Newly onset atrial fibrillation deserves to be investigated as an event of special interest in future trials with GLP-1 RA.

A randomized, open-label, controlled trial to evaluate the antimicrobial and surgical effect of CO2 laser treatment in diabetic infected foot ulcers: DULCIS (diabetic ulcer, CO2 laser, and infections) study.

AIM: Debridement of fibrin and necrotic tissue from the ulcer surface is an important component of the treatment of diabetic ulcers. A possible alternative to standard lancets is represented by CO2 laser, which vaporizes necrotic tissues together with any pathogen. The present trial is aimed at verifying the effect of a CO2 laser on bacterial load in the debridement of infected diabetic foot ulcers. METHODS: In this open-label randomized controlled trial (NCT02677779), patients with diabetes and an infected foot ulcers were randomized to either CO2 laser or traditional debridement. RESULTS: The reduction (%) of bacterial load with CO2 laser was significantly greater than in control group [-99.9 (-100.0; -90.0) vs. -50.0 (-96.0; -75.0), p = 0.049]. Similarly, a significantly greater reduction (%) of the fraction of ulcer area covered by fibrin was obtained in the intervention group [-84.1 (-95.0; -72.2) vs. -46.9 (-69.5; -40.8), p = 0.038]. CONCLUSIONS: Debridement of ulcers with CO2 laser significantly reduces bacterial load and fibrin-covered areas, and could be of help in the treatment of diabetic foot ulcer.

CO2 laser for the treatment of diabetic foot ulcers with exposed bone. A consecutive series of type 2 diabetic patients.

AIM: The treatment of foot ulcers with exposed bone is challenging, because of the risk of infection and of difficulties in the development of granulation tissue. A CO2 laser beam could be used to produce discontinuities in periosteum, allowing the exposure of blood containing multipotent stem cells, capable of initiating the healing process. The local application of platelet-rich plasma (PRP) has been proposed as a therapeutic tool for accelerating healing in foot ulcers, including those in patients with diabetes. Aim of the present pilot, proof-of-concept study is the assessment of the therapeutic potential of CO2 laser treatment, either alone or combined with PRP, in the treatment of diabetic foot ulcers with exposed bone. METHODS: We performed a pilot, uncontrolled 3-month observation study on a consecutive series of 9 type two diabetic patients and foot ulcers with exposed bone. A CO2-laser was used for producing nine discontinuities on periosteum for each cm2, by directing the focused laser beam on the bone until bleeding. The procedure was repeated up to 6 times, at a distance of 1 week and ulcers assessed weekly until the end of the study (3 months). In the last 5 of the 14 patients, the treatment described above was associated with PRP. RESULTS: Of the nine patients treated, four healed, and one more patient developed granulation tissue covering entirely bone surface. Out of the four patients who did not heal, one underwent minor amputation. Among the five patients treated with a combination of CO2 laser and PRP, two healed within 3 months, and two more patients developed granulation tissue covering entirely bone surface; the fifth patient did not show any improvement and underwent amputation. CONCLUSIONS: The present pilot experience represents a novelty in this field showing a possible use of CO2-laser in the treatment of diabetic foot ulcers.

Which is the main molecular target responsible for the cardiovascular benefits in the EMPA-REG OUTCOME trial? A journey through the kidney, the heart and other interesting places.

BACKGROUND: The results of the EMPA-REG-OUTCOME trial on type 2 diabetic patients at high risk for prior cardiovascular events showed that empagliflozin produces a remarkable reduction in the rates of hospitalization for heart failure (35%), cardiovascular death (38%), and all-cause death (32%). This unexpected cardio-protective action cannot be accounted for by the improvement of "classical" cardiovascular risk factors. AIMS: This review aims at summarizing current knowledge on the cardiovascular action of SGLT2 inhibitors and discuss the different hypotheses formulated to explain the results of the EMPA-REG-OUTCOME-study. DATA SYNTHESIS: We discuss in detail the major cardiovascular outcomes of the study in the light of the potential systemic and myocardial mechanisms of action of the drug. In addition, we propose and speculate on a direct effect of empagliflozin on cardiomyocytes. CONCLUSIONS: The available evidence is insufficient to establish any of the proposed mechanisms of cardiovascular action of empagliflozin. While awaiting for the results of ongoing clinical studies with other SGLT2 inhibitors, the most promising putative mechanisms still deserve to be confirmed with specifically designed, yet unavailable, pre-clinical studies.

How to define hypogonadism? Results from a population of men consulting for sexual dysfunction.

PURPOSE: The thresholds for testost erone (T) and the symptoms required for defining late onset hypogonadism (LOH) are under debate. The aims of the study are: (1) to verify the association between total and calculated free T (cfT) and sexual symptoms and (2) to identify thresholds for total and calculated free T to discriminate symptomatic from asymptomatic men. METHODS: A consecutive series of 4890 men attending the outpatient clinic for sexual dysfunction was retrospectively studied. Biochemical parameters were collected. The relationships between symptoms and total or calculated free T were evaluated as LOESS curves. RESULTS: Severe impairment in morning erections, low libido and ED were reported by 14.6, 2.7 and 60.2 %, respectively. Simultaneous presence of severe ED and impaired morning erections or low desire was reported by 12.7 and 1.9 %, respectively. Severely reduced desire and morning erections were complained of by 1.0 %. The simultaneous presence of the three severe sexual symptoms was reported by 0.8 %. Receiver operating characteristic (ROC) curve analysis showed that the highest accuracy for total T and cfT in detecting subjects with two symptoms was observed for reduced morning erections and desire (area under the ROC curve [AUC] = 0.670 ± 0.04 and 0.747 ± 0.04, for total T and cfT, respectively, both p < 0.0001). The addition of the third symptom, ED, further improved the accuracy (AUC = 0.681 ± 0.05 and 0.784 ± 0.04, for total T and cfT, respectively, both p < 0.0001). The assessment of the Youden index showed that the best thresholds for detecting men with androgen deficiency-related symptoms are 10.4 nmol/L for total T and ranges 225-260 pmol/L for cfT. CONCLUSIONS: The simultaneous presence of reduced morning erections and desire is the cluster of symptoms that, along with total T < 10.4 nmol/L or cfT <225 pmol/L, defines LOH in a specific, evidence-based manner.

Bringing the body of the iceberg to the surface: the Female Sexual Dysfunction Index-6 (FSDI-6) in the screening of female sexual dysfunction.

PURPOSE: Female Sexual Dysfunction (FSD) is a still poorly studied and underdiagnosed condition. The aim of the study was to produce an improved version of FSFI-6 (6-Item Version of the Female Sexual Function Index), entitled Female Sexual Dysfunction Index-6 (FSDI-6), and to estimate its accuracy as a screening instrument for FSD. METHODS: In the new version, an item related to the personal interest in having a satisfying sex life was added, while the item rating the entity of sexual arousal was removed. We administered FSDI-6 in a consecutive series of female adult patients not consulting for sexual problems (n = 120, Cohort 1), and in another series of patients specifically consulting for sexual problems, which were considered as the control group (n = 160, Cohort 2). RESULTS: FSDI-6 score was significantly higher in patients in Cohort 2 (p < 0.0001). Cronbach's alpha for FSDI-6 was 0.784, indicating a high level of reliability. The estimated area under the ROC curve for FSDI-6 was 0.657 (p < 0.0001, 95 % CI 0.584-0.730). The proportion of subjects with a pathological FSDI-6 score (≥16.5) was 29.9 (n = 32) and 59.4 % (n = 95) in Cohort 1 and 2, respectively (p < 0.0001). Among subjects with a pathological FSDI-6 (score ≥16.5), those consulting for FSD had been postmenopausal for fewer years, had a higher level of education, a lower BMI and a lower prevalence of chronic diseases than those not consulting for FSD (p < 0.05). CONCLUSIONS: Although a lower educational level, overweight/obesity, menopause and chronic diseases are risk factors for FSD, they are often associated with the failure in medical consultation for FSD. We propose that FSDI-6 should be performed by health care providers in non-specialist settings to detect potential FSD, which otherwise could remain under-diagnosed.

Testosterone supplementation and body composition: results from a meta-analysis of observational studies.

PURPOSE: The concept of testosterone (T) supplementation (TS) as a new anti-obesity medication in men with testosterone deficiency syndrome (TDS) is emerging. Data from placebo-controlled trials are more conflicting. The aim of this study is to systematically review and meta-analyze available observational and register studies reporting data on body composition in studies on TS in TDS. METHODS: An extensive MEDLINE, Embase, and Cochrane search was performed including the following words: "testosterone" and "body composition." All observational studies comparing the effect of TS on body weight and other body composition and metabolic endpoints were considered. RESULTS: Out of 824 retrieved articles, 32 were included in the study enrolling 4513 patients (mean age 51.7 ± 6.1 years). TS was associated with a time-dependent reduction in body weight and waist circumference (WC). The estimated weight loss and WC reduction at 24 months were -3.50 [-5.21; -1.80] kg and -6.23 [-7.94; -4.76] cm, respectively. TS was also associated with a significant reduction in fat and with an increase in lean mass as well as with a reduction in fasting glycemia and insulin resistance. In addition, an improvement of lipid profile (reduction in total cholesterol as well as of triglyceride levels and an improvement in HDL cholesterol levels) and in both systolic and diastolic blood pressure was observed. CONCLUSIONS: Present data support the view of a positive effect of TS on body composition and on glucose and lipid metabolism. In addition, a significant effect on body weight loss was observed, which should be confirmed by a specifically designed RCT.

Therapeutic implications of novel mutations of the RFX6 gene associated with early-onset diabetes.

Identification of the genetic defect underlying early-onset diabetes is important for determining the specific diabetes subtype, which would then permit appropriate treatment and accurate assessment of recurrence risk in offspring. Given the extensive genetic and clinical heterogeneity of the disease, high-throughput sequencing might provide additional diagnostic potential when Sanger sequencing is ineffective. Our aim was to develop a targeted next-generation assay able to detect mutations in several genes involved in glucose metabolism. All 13 known MODY genes, genes identified from a genome-wide linkage study or genome-wide association studies as increasing the risk of type 2 diabetes and genes causing diabetes in animal models, were included in the custom panel. We selected a total of 102 genes by performing a targeting re-sequencing in 30 patients negative for mutations in the GCK, HNF1α, HNF4α, HNF1ß and IPF1 genes at the Sanger sequencing analysis. Previously unidentified variants in the RFX6 gene were found in three patients and in two of them we also detected rare variants in WFS1 and ABCC8 genes. All patients showed a good therapeutic response to dipeptidyl peptidase-4 (DPP4) inhibitors. Our study reveals that next-generation sequencing provides a highly sensitive method for identification of variants in new causative genes of diabetes. This approach may help in understanding the molecular etiology of diabetes and in providing more personalized treatment for each genetic subtype.

Dipeptidyl peptidase-4 inhibitors and pancreatitis risk: a meta-analysis of randomized clinical trials.

AIM: Some observational studies reporting an increased risk of pancreatitis in association with Dipeptidyl Peptidase-4 inhibitors (DPP4i) have raised concerns on the overall safety of this class. Aim of the present meta-analysis is the systematic collection of information on pancreatitis in randomized clinical trials with DPP4i. DATA SOURCES: an extensive Medline, Embase and Cochrane Database search for 'vildagliptin', 'sitagliptin', 'saxagliptin', 'alogliptin', 'linagliptin' and 'dutogliptin' was performed up to 1 March 2013. STUDY SELECTION: studies were included if they satisfied the following criteria: (i) randomized trials, (ii) duration ≥12 weeks, (iii) on type 2 diabetes and (iv) comparison of DPP4i with placebo or active drugs. The identification and the selection of studies, and the subsequent data extraction were performed independently by two authors. Mantel-Haenszel odds ratio with 95% Confidence Interval (MH-OR) was calculated for all the adverse events defined below. The principal outcome was the effect of DPP4i on the incidence of pancreatitis. RESULTS: A total of 134 eligible trials were identified. The overall risk of pancreatitis and pancreatic cancer was not different between DPP4i and comparators (MH-OR: 0.93[0.51-1.69]; p = 0.82). CONCLUSIONS: It should be recognized that the number of observed cases of incident pancreatitis is small and the confidence intervals of risk estimates are wide. However, the present meta-analysis do not suggest any increase in the risk of pancreatitis with DPP4i.

Efficacy and safety of sodium glucose co-transport-2 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials.

AIMS: Sodium glucose co-transport-2 (SGLT-2) inhibitors, a new class of glucose-lowering agents, reduce tubular glucose reabsorption, producing a reduction of blood glucose without stimulating insulin release. The aim of the present meta-analysis is the assessment of the overall efficacy and safety profile of these drugs. METHODS: A meta-analysis was performed including all trials with a duration of at least 12 weeks, comparing a SGLT-2 inhibitor with a non-SGLT-2 inhibitor agent in type 2 diabetes. The principal outcome of this analysis was the effect of SGLT-2 inhibitors on HbA1c at 12, 24 and 52 weeks. Hypoglycaemia, genital and urinary infections were retrieved and combined to calculate Mantel-Haenszel odds ratio (MH-OR). Furthermore, data on body mass index (BMI), endpoint fasting plasma glucose, systolic and diastolic blood pressure, creatinine, hematocrit and lipid profile were collected. RESULTS: Among placebo-controlled trials, HbA1c reduction at 12, 24 and 52 weeks was 0.5 [0.4; 0.6], 0.6 [0.6; 0.5] and 0.6 [0.7; 0.5]%. In placebo-controlled studies, 24-week reduction of HbA1c with SGLT-2 inhibitors was greater in trials enrolling patients with a lower mean age and duration of diabetes, and a higher baseline BMI, HbA1c and fasting glucose. In placebo-controlled trials, SGLT-2 inhibitors determined a weight loss during the first 24 weeks, which was maintained up to 52 weeks. CONCLUSIONS: SGLT-2 inhibitors are effective in the treatment of type 2 diabetes, providing additional benefits, such as weight loss, reduction of blood pressure and increase in high-density lipoprotein (HDL)-cholesterol. Apart from genital and urinary infections, rather frequent but usually mild, SGLT-2 inhibitors appear to be well tolerated.