Glucagon-like peptide-1 receptor agonists and risk of thyroid cancer: A systematic review and meta-analysis of randomized controlled trials.

AIM: To conduct a meta-analysis of randomized clinical trials (RCTs) to investigate whether there is an association between glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment and thyroid cancer. MATERIALS AND METHODS: In this meta-analysis of RCTs, we included studies comparing a GLP-1RA with any comparator, lasting at least 52 weeks, and reporting the incidence of adverse events independently of the principal endpoint and population. All cases of thyroid cancer were collected. RESULTS: We retrieved 64 trials, 26 of which reported at least one incident case of thyroid cancer. GLP-1RA treatment was associated with a significant increase in the risk of overall thyroid cancer (Mantel-Haenzel odds ratio [MH-OR] 1.52 [95% confidence interval {CI} 1.01, 2.29]; P = 0.04, I2 = 0%), with a fragility index of 1, and a 5-year number needed to harm of 1349. The association remained significant when including only trials lasting at least 104 weeks (MH-OR 1.76 [95% CI 1.00, 3.12]; P = 0.05). No significant association was found for papillary thyroid cancer (MH-OR 1.54 [95% CI 0.77, 3.06]; P = 0.22) or medullary thyroid cancer (MH-OR 1.44 [95% CI 0.23, 9.16]; P = 0.55). CONCLUSIONS: Our meta-analysis showed that GLP-1RA treatment could be associated with a moderate increase in relative risk for thyroid cancer in clinical trials, with a small increase in absolute risk. Studies of longer duration are required to assess the clinical implications of this finding.

Effects of glucose-lowering agents on cardiovascular and renal outcomes in subjects with type 2 diabetes: An updated meta-analysis of randomized controlled trials with external adjudication of events.

AIMS: To investigate the effects of glucose-lowering agents on all-cause mortality, and cardiovascular and renal outcomes in adults with type 2 diabetes. METHODS: A MEDLINE and EMBASE search was performed to identify randomized controlled trials, published up to 28 February 2022, with a follow-up ≥52 weeks, in which glucose-lowering drugs were compared with either placebo or active comparators. We included only trials reporting formal external adjudication of events. All-cause mortality, 3-point MACE (major cardiovascular events), and hospitalization for heart failure (HHF) were considered as principal outcomes. Doubling of serum creatinine, worsening albuminuria, and renal death were considered as secondary endpoints. RESULTS: We included randomized controlled trials performed on metformin (n = 17), pioglitazone (n = 20), alpha-glucosidase inhibitors (n = 9), insulin secretagogues (n = 42), dipeptidyl-peptidase-4 inhibitors (n = 67), glucagon-like peptide-1 receptor agonists (n = 45) or sodium-glucose co-transporter-2 inhibitors (SGLT-2i; n = 42) and insulin (n = 18). Glucagon-like peptide-1 receptor agonist and SGLT-2i were associated with a significant reduction in all-cause mortality [Mantel-Haenszel odds ratio (MH-OR), 95% confidence interval: 0.88 (0.83; 0.95) and 0.85 (0.79; 0.91), respectively] and MACE [MH-OR, 95% confidence interval: 0.89 (0.84; 0.94) and 0.90 (0.84; 0.96), respectively]. SGLT-2i was associated with a reduced risk of HHF [MH-OR 0.68 (0.62; 0.75)], worsening albuminuria [MH-OR 0.67 (0.55; 0.80)] and doubling of serum creatinine [MH-OR 0.58 (0.44; 0.79)]. Metformin and pioglitazone were associated with a significantly lower risk of MACE [MH-OR 0.60 (0.47; 0.80) and 0.85 (0.74; 0.97), respectively] and pioglitazone with a higher risk of HHF [MH-OR 1.30 (1.04; 1.62)]. Insulin secretagogues were associated with increased risk of all-cause mortality [MH-OR 1.12 (1.01; 1.24)] and MACE [MH-OR 1.19 (1.02; 1.39)]. CONCLUSIONS: The results of this updated meta-analysis need to be considered in the choice of drug treatment for type 2 diabetes mellitus, which cannot be merely based on the effect of glucose-lowering drugs on long-term glycaemic control.

Metabolic bariatric surgery as a therapeutic option for patients with type 2 diabetes: A meta-analysis and network meta-analysis of randomized controlled trials.

AIM: To compare different types of metabolic surgery with non-surgical therapy for the treatment of type 2 diabetes (T2D). METHODS: The present network meta-analysis (NMA) includes randomized clinical trials (duration ≥ 52 weeks) comparing different surgery techniques with non-surgical therapy in diabetes patients. The primary endpoints were endpoint HbA1c, body mass index (BMI) and diabetes remission. The secondary endpoints included fasting plasma glucose, lipid profile, blood pressure, arterial hypertension and dyslipidaemia remission, quality of life and surgical adverse events. Indirect comparisons of different types of surgery were performed by NMA. Mean and 95% confidence intervals for continuous variables, and the Mantel-Haenzel odds ratio for categorial variables, were calculated. RESULTS: The types of surgical procedure included laparoscopic adjustable gastric banding, Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), bilio-pancreatic diversion (BPD), greater curvature plication (GCP), one-anastomosis gastric bypass (OAGB) and Duodeno-Jejunal bypass. Thirty-six trials were included. Metabolic bariatric surgery (MBS) was associated with a significantly higher reduction of HbA1c, diabetes remission and BMI compared with medical therapy. In the NMA, a significant reduction of HbA1c was observed with OAGB and SG. Complete diabetes remission significantly increased with all surgical procedures in comparison with non-surgical therapy, except for GCP. In addition, only BPD, RYGB and OAGB were associated with a significant reduction of BMI. CONCLUSIONS: MBS is an effective option for the treatment of T2D in patients with obesity. Further long-term trials of appropriate quality are needed for assessing the risk-benefit ratio in some patient cohorts, such as those with a BMI of less than 35 kg/m2 and aged older than 65 years.

Effects of insulin on cardiovascular events and all-cause mortality in patients with type 2 diabetes: A meta-analysis of randomized controlled trials.

AIM: In 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. This expert panel, after identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs), all-cause mortality, and hospitalization for heart failure (HHF) as critical outcomes, decided to perform a systematic review and meta-analysis on the effect of insulin with this respect. DATA SYNTHESIS: A MEDLINE database search was performed to identify all RCTs, up to June 1st, 2021, with duration≥52 weeks, in which insulin was compared with either placebo or active comparators. The principal endpoints were MACE and HHF (restricted for RCT reporting MACEs within their outcomes), all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered. Six RCTs (enrolling 8091 patients and 10,139 in the insulin and control group, respectively) were included in the analysis for MACEs and HF, and 18 in that for all-cause mortality (9760 and 11,694 patients in the insulin and control group, respectively). Treatment with insulin neither significantly increased nor reduced the risk of MACE, all-cause mortality, and HHF in comparison with placebo/active comparators (MH-OR: 1.09, 95% CI 0.97-1.23; 0.99, 95% CI 0.91, 1.08; and 0.90, 95% CI 0.78, 1.04, respectively). CONCLUSIONS: This meta-analysis showed no significant effects of insulin on incident MACE, all-cause mortality, and HHF.

All-cause mortality and cardiovascular events in patients with type 2 diabetes treated with alpha-glucosidase inhibitors: A meta-analysis of randomized controlled trials.

AIM: Alpha-glucosidase inhibitors are approved drugs for treating type 2 diabetes (T2DM); however, their effects on mortality and cardiovascular safety are unclear. This meta-analysis was aimed at evaluating the effects of alpha-glucosidase inhibitors on all-cause mortality and major cardiovascular events (MACE). DATA SYNTHESIS: A Medline, Embase, Cochrane database searching for alpha-glucosidase inhibitors was performed up to July 1st, 2021. All randomized controlled trials (RCT) with a duration ≥52 weeks and comparing the effects of alpha-glucosidase inhibitors with placebo or active drugs were collected. Further inclusion criteria were: RCT reporting MACE within their primary outcome, or as pre-defined secondary outcome; and RCT enrolling at least 100 patients with T2DM. Mantel-Haenszel odds ratio (MH-OR) with 95% confidence intervals were calculated for the aforementioned outcomes. A total of eight RCTs, enrolling 1124 and 908 patients on alpha-glucosidase inhibitors and comparators, respectively, were identified. No trials reported information on MACE. Treatment with alpha-glucosidase inhibitors was not associated with a significant increase of all-cause mortality compared with other therapies or no therapy/placebo (MH-OR 0.76 [0.28; 2.05]). CONCLUSIONS: The evidence of beneficial or detrimental effects of alpha-glucosidase inhibitors on all-cause mortality and cardiovascular events is not sufficient to draw any conclusions.

Effects of pioglitazone on cardiovascular events and all-cause mortality in patients with type 2 diabetes: A meta-analysis of randomized controlled trials.

AIM: In 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. After identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs), all-cause mortality, and hospitalization for heart failure (HHF) as critical outcomes, the experts decided to perform a systematic review and meta-analysis on the effect of pioglitazone with this respect. DATA SYNTHESIS: A MEDLINE database search was performed to identify RCTs, up to June 1st, 2021, with duration≥52 weeks, in which pioglitazone was compared with either placebo or active comparators. The principal endpoints were MACE and HHF (restricted for RCT reporting MACEs within their outcomes), all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered. Eight RCTs were included in the analysis for MACEs and HF (5048 and 5117 patients in the pioglitazone and control group, respectively), and 24 in that for all-cause mortality (10,682 and 9674 patients). Pioglitazone neither significantly increased nor reduced the risk of MACE, all-cause mortality, and HHF in comparison with placebo/active comparators (MH-OR: 0.90, 95% CI 0.78-1.03, 0.91, 95% CI 0.77, 1.09, and 1.16, 95% CI 0.73, 1.83, respectively). Pioglitazone was associated with a significant reduction of MACE in patients with prior cardiovascular events (MH-OR 0.84, 95% CI 0.72-0.99). CONCLUSIONS: This meta-analysis showed no significant effects of pioglitazone on incident MACE, all-cause mortality, and HHF.

Self-management in patients with type 2 diabetes: Group-based versus individual education. A systematic review with meta-analysis of randomized trails.

AIM: Patient education is an essential component of the treatment of type 2 diabetes mellitus (T2DM). The present meta-analysis was aimed at verifying the efficacy of group-based versus individual education for self-management in patients with T2DM. DATA SYNTHESIS: A Medline and Embase search up to January 1st, 2021, was performed, including Randomized Controlled Trials (RCT) with duration>6 months, enrolling patients with T2DM and comparing individual-based with group-based educational programs. The primary outcome was endpoint HbA1c; secondary endpoints were lipid profile, body weight, blood pressure, patients' adherence/knowledge, and quality of life. The weighed difference in means (WMD) and Mantel-Haenzel Odds Ratio (MH-OR), with 95% Confidence Interval (CI), were calculated. We retrieved 14 RCT. No significant between-group difference in HbA1c (WMD -0.39[-0.89; 0.09] mmol/mol, p = 0.11) was observed. At metaregression analyses, longer trial duration, higher baseline mean age and duration of diabetes, and lower baseline HbA1c were correlated with greater efficacy of group-based programs in reducing HbA1c. When analyzed separately, trials excluding insulin-treated patients showed a significant reduction of HbA1c in favor of group education. CONCLUSIONS: In patients with T2DM, group education has similar efficacy as individual education on glucose control. Group programs are associated with an improved quality of life and patients' knowledge. PROSPERO AND OSF REGISTRATION: ID243149.

Sodium-glucose co-transporter-2 inhibitors and all-cause mortality: A meta-analysis of randomized controlled trials.

The present meta-analysis is aimed at assessing the effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors on all-cause mortality and differences across different trials and molecules of the class. We included all randomized clinical trials with a duration of treatment longer than 52 weeks, enrolling at least 100 patients in each arm, and comparing an SGLT2 inhibitor with any comparator or placebo. Out of 139, 235 and 145 items identified, 21 trials were selected, enrolling 39 593 and 30 771 patients in SGLT2 inhibitor and comparator arms, respectively, with a median duration of 104 weeks, and reporting 2474 and 2298 deaths for SGLT2 inhibitors and comparators, respectively. No relevant heterogeneity was found (I2 = 17%). Treatment with SGLT2 inhibitors was associated with a significant reduction in all-cause mortality (MH-OR [95% CI] 0.86 [0.81, 0.91] P < .00001). Meta-regression analyses found a significant direct association of treatment effect only with the proportion of Asian subjects enrolled, and an inverse correlation with the proportion of Caucasian patients. In conclusion, SGLT2 inhibitors reduce all-cause mortality in randomized controlled trials.

Comparison between different types of exercise training in patients with type 2 diabetes mellitus: A systematic review and network metanalysis of randomized controlled trials.

AIM: Aim of the present meta-analysis and network metanalysis (NMA) is the assessment of the effects of physical exercise on glucose control and cardiovascular risk factors in type 2 diabetes. DATA SYNTHESIS: This metanalysis includes all available trials exploring the effects of different exercise modalities in type 2 diabetes, with a duration of ≥3 months. The standardized difference in means (SDM) with 95% Confidence Intervals were calculated. Data were analyzed using MetaXL and Rev Man 5.0. Primary endpoint was the effect of exercise versus no exercise on HbA1c and fasting plasma glucose (FPG) at endpoint. Secondary endpoints were body weight and fat, waist circumference, and blood pressure. A comparison of different exercise training modalities (aerobic, resistance and combined) for the same endpoints was also performed, choosing 'no exercise' as the reference for indirect comparisons. We included 25 trials fulfilling all inclusion criteria. Physical exercise versus no exercise produced a small, but significant, improvement of HbA1c, body fat, and systolic blood pressure at endpoint (-0.3 [-0.1;-0.4]%, -1.44 [-2.22, -0.66]%, and -5.6 [-9.5, -1.6] mmHg, respectively). Combined, supervised aerobic and resistance exercise were associated with a significantly greater reduction of HbA1c (SDM, -0.4 [-0.6;-0.3], -0.2 [-0.4;-0.1], and -0.2 [-0.3;-0.1]%, respectively), but not of FPG, in comparison with no exercise. CONCLUSIONS: Physical exercise produces small, but detectable, advantages on glycemic control and cardiovascular risk factors and should be suggested in type 2 diabetes. Combined aerobic/resistance training seems to be superior to aerobic training alone, but differences are small and the reliability of supporting evidence limited.

Sars-CoV2 vaccine hesitancy in Italy: A survey on subjects with diabetes.

BACKGROUND AND AIMS: Vaccine Hesitancy (VH) is a relevant obstacle for the COVID-19 vaccination campaign. The aim of this study is to assess the proportion of subjects unwilling to vaccinate among patients with type 1 (T1DM) and 2 (T2DM) diabetes, exploring factors associated with VH. METHODS AND RESULTS: A purposely created interview was delivered from physicians to a consecutive series of adult (>18 years) subjects with diabetes referring to the Diabetes Outpatient Clinic of Careggi Hospital, Florence, from January 1st to April 30th 2021. Out of 502 subjects enrolled, 92 were vaccine hesitant respondents (18.3%); the corresponding figure for T1DM and T2DM was 13.0% (N = 14), and 19.9% (N = 78), respectively. After adjusting for age, higher HbA1c (1.07 [1.02-1.13], p = 0.008) and triglycerides levels (1.03 [1.01-1.06], p = 0.011) were positively associated with VH, among patients with T1DM. At multivariate analysis, after adjusting for age, creatinine, and statin use, patients with T2DM affected by obesity (9.98 [4.89-9.59], p < 0.01) and with lower levels of creatinine (0.36 [0.21-0.54], p = 0.029) were more likely to refuse COVID vaccination. CONCLUSIONS: Hesitancy toward COVID-19 vaccination among subjects with diabetes is not negligible and seems to be more prevalent in individuals with lower adherence to medical prescriptions and/or reduced concerns over their health. This suggests the need for specific interventions to increase awareness and counter prejudices on vaccines.

Improvement of glycemic control in type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials.

AIM: Different guidelines provide similar, but not identical, therapeutic targets for HbA1c in type 2 diabetes. These targets can also depend from the different pharmacological strategies adopted for intensifying glycemic control. DATA SYNTHESIS: This meta-analysis includes randomized trials adopting any pharmacological regimen for intensifying glycemic control in T2DM (versus standard of care/placebo), with a trial duration ≥2 years and a between-group HbA1c difference≥0.5%. The primary outcome was to assess the effects of the improvement of glycemic control on major cardiovascular events (MACE), ocular and renal complications, and severe hypoglycemia. Mantel-Haenszel odds ratios (MH-OR) with 95% Confidence Intervals were calculated for all the outcomes considered. We included 13 trials fulfilling the inclusion criteria. The improvement of glycemic control was associated with a lower risk of MACE (MH-OR:0.89 [95%CI 0.85-0.94]) and renal adverse events (MH-OR 0.73 [0.65-0.82]), but not all-cause mortality (MH-OR 0.95 [0.88-1.01]) and ocular adverse complications (MH-OR 0.94 [0.72-1.22]). For glucose-lowering drugs inducing hypoglycemia, a protective effect on the risk of microvascular complications, but not of MACE and all-cause mortality, was observed only for HbA1c ≤ 48 mmol/mol, but with higher risk of severe hypoglycaemia (MH-OR 2.72 [1.79-4.13]). Drugs not inducing hypoglycaemia were associated with a reduction of MACE, renal adverse events, and all-cause mortality, for HbA1c< 7% (no data for lower targets). CONCLUSIONS: The present meta-analysis show that the improvement of glycemic control with drugs not inducing hypoglycemia is associated with a reduction in the risk of long-term chronic vascular and renal complications, and all-cause mortality.

Efficacy and effects of bariatric surgery in the treatment of obesity: Network meta-analysis of randomized controlled trials.

AIMS: Bariatric surgery (BS) is recommended for subjects with a Body Mass Index (BMI) over of 40 kg/m2 or with a BMI between 35 and 40 kg/m2 with obesity-related comorbidities. Aim of the study was to compare different types of BS with medical therapy (MT) for the treatment of obesity. DATA SYNTHESIS: We conducted a network-meta-analysis (NMA) including randomized clinical trials comparing different BS techniques versus MT in people with obesity, with a duration ≥24 weeks (PROSPERO, #CRD42020160359). Primary endpoint was BMI. Indirect comparisons of different types of surgery were performed by NMA. Types of BS included: laparoscopic adjustable gastric banding (LAGB), Roux-en-Y gastric bypass, sleeve gastrectomy (SG), bilio-pancreatic diversion (BPD); greater curvature plication (GCP); one-anastomosis gastric bypass (OAGB); Laparoscopic Vertical Banded Gastroplasty (LVBG) and duodenal switch (DS). 43 trials were retrieved in this metanalysis. BS was associated with a significant reduction in BMI, systolic blood pressure, triglyceride and fasting glucose, and with a significant increase of HDL cholesterol when compared to MT. In direct comparisons, RYGB was more effective than LAGB, LVBG, and GCP, but less effective than DS, whereas LAGB was less effective than LVBG and SG. In the NMA, DS and BPD appeared to be more effective than other procedures. CONCLUSIONS: BS produces a greater weight loss than MT in morbidly obese patients, inducing a greater improvement of obesity-associated metabolic parameters. Available data are insufficient to assess the effect of BS on mortality. Different surgical procedures are heterogeneous for efficacy and safety.

Effect of metformin on all-cause mortality and major adverse cardiovascular events: An updated meta-analysis of randomized controlled trials.

AIMS: The Italian Society of Diabetology and the Italian Association of Clinical Diabetologists are developing new guidelines for drug treatment of type 2 diabetes. The effects of anti-hyperglycaemic drugs on all-cause mortality and major adverse cardiovascular events (MACEs) were included among the critical clinical outcomes. We have therefore carried out an updated meta-analysis on the effects of metformin on these outcomes. DATA SYNTHESIS: A MEDLINE and EMBASE search was performed to identify all randomized controlled trials (RCTs) with duration ≥52 weeks (published up to August 2020), in which metformin was compared with either placebo/no therapy or active comparators. MACEs (restricted for RCT reporting MACEs within their study endpoints) and all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified endpoints) were considered as the primary endpoints. Mantel-Haenszel odds ratio (MH-OR) with 95% confidence interval was calculated for all endpoints considered. Metformin was associated with a nonsignificant reduction of all-cause mortality (n = 13 RCTs; MH-OR 0.80 [95% CI 0.60, 1.07]). However, this association became statistically significant after excluding RCTs comparing metformin with sulfonylureas, SGLT-2 inhibitors or GLP-1 analogues (MH-OR 0.71 [0.51, 0.99]). Metformin was associated with a lower risk of MACEs compared with comparator treatments (n = 2 RCTs; MH-OR 0.52 [0.37, 0.73]), p < 0.001. Similar results were obtained in a post-hoc analysis including all RCTs fulfilling criteria for inclusion in the analysis (MH-OR: 0.57 [0.42, 0.76]). CONCLUSIONS: This updated meta-analysis suggests that metfomin is significantly associated with lower risk of MACEs and tendentially lower all-cause mortality compared to placebo or other anti-hyperglycaemic drugs.

Cardiovascular events and all-cause mortality in patients with type 2 diabetes treated with dipeptidyl peptidase-4 inhibitors: An extensive meta-analysis of randomized controlled trials.

AIMS: Meta-analyses of randomized trials on Dipeptidyl Peptidase-4 inhibitors (DPP4i) reported discordant results on major cardiovascular events (MACE), mortality, and heart failure. Aim of this meta-analysis of randomized trials is the assessment of the cardiovascular safety of DPP4i. DATA SYNTHESIS: A Medline, Embase, Cochrane database search for sitagliptin, vildagliptin, omarigliptin, saxagliptin, alogliptin, trelagliptin, anagliptin, linagliptin, gemigliptin, evogliptin, and teneligliptin was performed up to up January 1st, 2020. All trials with a duration ≥24 weeks and comparing the effects of DPP4i with placebo or active drugs were collected. Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all outcomes defined above. A total of 182 eligible trials were identified. DPP-4i were not associated with an increased risk of MACE (MH-OR 0.99 [0.93, 1.04]), all-cause mortality (MH-OR 0.99 [0.93, 1.06]), and heart failure (MH-OR 1.05 [0.96, 1.15]) with no significant differences across individual molecules, except for saxagliptin, which was associated with an increased risk of heart failure. CONCLUSIONS: As a class, DPP4i are not associated with any increase or reduction of MACE, all-cause mortality, and heart failure. Saxagliptin seems to be associated with an increased risk of hospitalization for heart failure.

Efficacy and safety of glucose-lowering agents in patients with type 2 diabetes: A network meta-analysis of randomized, active comparator-controlled trials.

AIM: Aim of the present network meta-analysis (NMA) is the comparison across glucose-lowering drugs (GLA) concerning their effects on glucose control, body weight, hypoglycemia, gastrointestinal adverse events, and quality of life. DATA SYNTHESIS: This NMA includes randomized clinical trials comparing different head-to-head comparison trials with EMA-approved GLA in type 2 diabetes, with a duration of ≥52 weeks. All drugs have to be administered at the maximal approved dose. Primary endpoints were HbA1c at 12, 52, and 104+ weeks. Secondary endpoints were body weight, quality of life, hypoglycemia, and gastrointestinal disorders. Indirect comparisons of different GLA were performed by NMA choosing metformin as reference. The standardized difference in means (SDM) and Mantel-Haenzel Odds Ratio [MH-OR] (using random-effect models) with 95% Confidence Intervals were calculated for categorical and continuous variables, respectively. We included 68 trials fulfilling all inclusion criteria. At 12 weeks, when considering indirect comparisons, insulin secretagogues (IS) were associated with a significantly greater reduction in comparison with metformin (SDM, -0.3 [-0.4;-0.2]%); a significantly lower efficacy was observed for pioglitazone. At 52 weeks, IS were no longer associated with a greater reduction of HbA1c; whereas a significant decrease in HbA1c was observed for GLP-1 RA (SDM, -0.2 [-0.1;-0.3]%). At 104+ weeks, only SGLT-2 inhibitors showed a significantly greater HbA1c reduction (SDM, -0.2 [-0.1;-0.3]%), whereas sulfonylureas and insulin showed a significantly lower efficacy (SDM, 0.1 [0.0; 0.2]%), and 0.4 [0.3; 0.5]%, respectively). CONCLUSIONS: The results of this meta-analysis should be considered together with evidence on long-term outcomes for selecting the most appropriate drugs for individual patients.

Are diabetes and its medications risk factors for the development of COVID-19? Data from a population-based study in Sicily.

BACKGROUND AND AIMS: Diabetes mellitus (DM) has been associated with higher incidence of severe cases of COVID-19 in hospitalized patients, but it is unknown whether DM is a risk factor for the overall COVID-19 incidence. The aim of present study was to investigate whether there is an association of DM with COVID-19 prevalence and case fatality, and between different DM medications and risk for COVID-19 infection and death. METHODS AND RESULTS: retrospective observational study on all SARS-CoV-2 positive (SARS-CoV-2+) cases and deaths in Sicily up to 2020, May 14th. No difference in COVID-19 prevalence was found between people with and without DM (RR 0.92 [0.79-1.09]). Case fatality was significantly higher in SARS-CoV-2+ with DM (RR 4.5 [3.55-5.71]). No diabetes medication was associated with differences in risk for SARS-Cov2 infection. CONCLUSIONS: in Sicily, DM was not a risk factor for COVID-19 infection, whereas it was associated with a higher case fatality.

Association between different screening strategies for SARS-CoV-2 and deaths and severe disease in Italy.

BACKGROUND: The WHO recommends testing any suspected person with Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2), in order to limit the spread of the epidemic. In Italy, some Regions opted for extensive testing, whereas others limited tests to selected subjects. To assess the influence of different strategies, we examined the incidence of death and severe cases in Italy. METHODS: Data on new cases of SARS-CoV-2, number of tests, deaths and admissions to Intensive Care Units (ICU) were retrieved in each Italian Region, from 24 February to 18 March 2020. As an index of different screening strategies, the number of tests/positive test results (P/T) ratio as of 7 March 2020, was considered. The cumulative number of deaths and of new severe cases, between March 23 and 25 was recorded. The association of those two outcomes with the number of P/T ratio was assessed using linear regression models. RESULTS: In the interval between March 23 and 25, recorded deaths (*million inhabitants) were 14 (3-54), whereas severe cases were 31 (10-112). Both the number of deaths and that of severe cases showed a significant correlation (R2 .57 and .41, with P < .01) with the P/T ratio. Deaths and severe cases were associated with higher mean personal income and lower density of General Practioners (GPs). The association of P/T with severe cases and deaths retained statistical significance after adjusting for mean personal income (R2 .30 and .41, respectively; both P = .04) and GPs density (R2 .21 and .19, respectively; both P = .03). CONCLUSIONS: A more aggressive screening strategy for SARS-Cov-2, was associated with lower rates of death and severe disease in Regions of Italy.

Alpha-tocopherol and contrast-induced nephropathy: A meta-analysis of randomized controlled trials.

Background: Contrast-induced nephropathy (CIN) is a relevant cause of acute renal dysfunction and is associated with an increased morbidity and mortality. Purpose: Verify the effect of α-tocopherol pre-treatment on CIN prevention in subjects with chronic kidney disease. Methods: A Medline/Embase and clinicaltrials.gov were searched up to May 1st, 2017. Randomized controlled trials recruiting patients undergoing diagnostic or therapeutic radiocontrast infusion comparing the effect of either oral or i.v. multiple administration of pharmacological dose of α-tocopherol in preventing CIN versus placebo were included. A random-effects model, calculating Mantel-Haenszel odds ratio with 95% confidence interval, was applied to study the effect of α-tocopherol on CIN occurrence. Funnel plot analysis was used to assess publication bias, while agreement within studies was measured by the I2 index and tested with the Q-Cochran test. Results: Out of 242 studies, 4 trials were selected. CIN incidence resulted significantly lower in α-tocopherol compared to placebo group (5.8% vs. 15.4%, MH-OR [95% C.I.] 0.34 [0.19 - 0.59]). Alpha-tocopherol treatment was associated with both a tendential higher eGFR (mean difference 2.19 [95% C.I. -0.41; 4.79] mL/min) and lower creatinine level (mean difference -0.06 [95% C.I. -0.21; 0.09] mg/dl) compared to placebo. No relevant publication bias (p = 0.48) and heterogeneity (I2 = 0%; χ2 = 1.01, df = 3 [p = 0.80], I2 = 0%) were evident. Conclusions: Alpha-tocopherol pre-treatment is associated with reduction of incidence of CIN. Its administration deserves to be further explored as a simple and inexpensive tool for CIN prevention.

Metabolic surgery for the treatment of type 2 diabetes: A network meta-analysis of randomized controlled trials.

AIM: To compare different types of metabolic surgery (MS) with medical therapy (MT) for the treatment of type 2 diabetes (T2D). MATERIALS AND METHODS: We conducted a network-meta-analysis (NMA) including randomized clinical trials comparing different MS techniques versus MT in people with T2D, with a duration of ≥24 weeks. Primary endpoints were glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and diabetes remission. Indirect comparisons of different types of surgery were performed by NMA. Mean and 95% confidence intervals for continuous variables, and Mantel-Haenzel odds ratios for categorial variables, were calculated using random effect models. Types of MS included: laparoscopic adjustable gastric banding (LAGB), Roux-en-Y gastric bypass, sleeve gastrectomy (SG), bilio-pancreatic diversion (BPD); greater curvature plication (GCP); one-anastomosis gastric bypass (OAGB); and duodenojejunal bypass. RESULTS: The 24 retrieved trials included 1351 patients (1014 with MS and 337 with MT). The mean baseline BMI was 36.8 kg/m2 . MS was associated with significantly greater reductions in HbA1c and FPG and greater diabetes remission when compared to MT. In the NMA, a significant reduction in HbA1c was observed with OAGB and SG. All surgical procedures were associated with a significant increase in diabetes remission, except GCP and LAGB. All procedures were associated with a reduction of body mass index (BMI). CONCLUSIONS: Metabolic surgery is an interesting option for the treatment of T2D, although further data are needed to demonstrate its long-term efficacy and safety. Present data are not sufficient to modify current recommendations, which consider MS a possible treatment for T2D in those with a BMI >35 kg/m2 .

Fournier's gangrene and sodium-glucose co-transporter-2 inhibitors: A meta-analysis of randomized controlled trials.

Fournier's gangrene (FG) is a rare, life-threatening necrotizing fasciitis of the perineum. The US Food and Drug Administration (FDA) released a Drug Safety Communication regarding the risk of FG associated with sodium-glucose co-transporter-2 inhibitors (SGLT2i), relying on the FDA Adverse Event Reporting System. To verify this association, we performed a meta-analysis of all randomized controlled trials enrolling patients with type 2 diabetes, comparing SGLT2i with placebo or different therapies, collecting cases of FG reported as a serious adverse event. Risk of abscess, cellulitis and erysipela were secondary outcomes. We retrieved 84 trials enrolling 42 415 patients in the SGLT2i group and 27 158 patients in comparator groups. No difference was observed between SGLT2i and comparators in the risk of FG (Mantel-Haenzel odds ratio [MH-OR] 0.41 [0.09, 1.82]), abscess (MH-OR 0.94 [0.54, 1.65]), cellulitis (MH-OR 0.90 [0.71, 1.13] or erysipela (MH-OR 0.89 [0.45, 1.77]). The number of events was small, leading to a wide confidence interval that does not allow ruling out an increase in FG or skin and subcutaneous tissue infections.