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• Italy was the European epicentre of the COVID-19 pandemic, with a high number of cases and deaths. • The number of excess deaths in comparison with the same months from previous years was higher than the recorded COVID-19-related deaths. • The impact of COVID-19 on mortality was greater than that indicated by official counts of victims. • Causes of death other than COVID-19 could have contributed to the increase in overall mortality rates. • Diabetes prevalence, general practitioners' density, proportion of elderly in nursing homes, and extensive testing could explain the regional differences in excess mortality. The number of excess deaths during February–March 2020 in Italy, in comparison with previous years, was considerably higher than the recorded COVID19-related deaths. The present study aimed to explore the association of excess mortality with some indices related to the COVID-19 pandemic and its management. Data on all-cause mortality from 20 February–31 March in the years 2015–2020, and demographic, socioeconomic and healthcare organisation data of each Italian region were obtained from the Italian Institute of Statistics. Non-COVID-19-Imputed Excess Mortality (NCIEM) was calculated as the difference between the excess 2020 mortality and reported COVID-19 mortality. The association of NCIEM with the rate of COVID-19 cases, COVID-19 mortality and other potential moderators was assessed using linear regression models. The nationwide number of excess deaths and COVID-19 deaths was 26,701 and 13,710, respectively, with a difference of 12,991. The NCIEM in different regions showed a direct correlation with COVID-19 mortality (r 2 = 0.61, p < 0.001) and total cases (r 2 = 0.30, p = 0.012), and an inverse correlation with cases/total tests ratio (r 2 = 0.49, p = 0.001). Direct correlations were also found with the proportion of institutionalised elderly, whereas inverse correlations were observed with prevalence of diabetes, cardiovascular mortality and density of general practitioners. The impact of the COVID-19 pandemic on all-cause mortality was considerably greater than that indicated by official counts of victims. Limited testing capacity and causes of death other than COVID-19 could have contributed to the increase in overall mortality rates. [ABSTRACT FROM AUTHOR]

Aims: Observational studies and meta-analyses of randomized trials on dipeptidyl peptidase-4 inhibitors (DPP4i) reported discordant results on the risk of malignancies with this class of drugs. Aim of the present meta-analysis is the assessment of the effect of DPP4i treatment on the incidence of different types of cancer, collecting all available evidence from randomized controlled trials. Methods: An extensive MEDLINE, EMBASE, and Cochrane database search for sitagliptin or vildagliptin or omarigliptin or saxagliptin or alogliptin or trelagliptin or anagliptin or linagliptin or gemigliptin or evogliptin or teneligliptin was performed up to September 30th, 2019. All trials performed on type 2 diabetes, with duration ≥ 24 weeks, and comparing of DPP4i with placebo or active drugs were collected. The study has been registered on PROSPERO (#153344). Mantel–Haenszel odds ratio (MH-OR) with 95% confidence interval (95% CI) was calculated for all outcomes. Results: A total of 157 eligible trials were identified. DPP-4i were not associated with an increased risk of overall cancer (MH-OR 0.93 [0.86, 1.00]; p = 0.07), with no significant differences across individual molecules of the class. When compared with placebo/none, a lower risk of cancer with DPP-4i was observed in placebo-controlled trials (MH-OR 0.90 [0.82, 0.99], p = 0.030), whereas no significant differences have been detected with any other comparators. DPP-4i was associated with a significant reduction in colorectal cancer (MH-OR 0.70 [0.53, 0.94], p = 0.020). Conclusions: Available data do not support the hypothesis of an association of DPP4i treatment with malignancies, with a possible beneficial effect for colon-rectal cancer. [ABSTRACT FROM AUTHOR]

Aim: The aim of this meta‐analysis of randomized trials was to assess the effects of SGLT‐2i on the overall incidence of malignancies and on different types of cancer, summerizing the results of trials with a duration of at least 1 year. This was done in light of the effect of SGLT‐2 inhibitors (SGLT‐2is) that has been highlighted by some studies, showing an increased incidence of bladder cancer, particularly with use of empagliflozin. Materials and methods: A Medline and Embase search for "Canaglifozin", "Dapaglifozin", "Empaglifozin", "Ertuglifozin", "Ipraglifozin", Tofoglifozin" or "Luseoglifozin" was performed, identifying randomized trials with a duration of more than 52 weeks up to 1 December 2018 that compared SGLT‐2is with placebo or active comparators. The outcomes considered were all types of cancer and several site‐specific cancers (ie, breast, pulmonary, gastrointestinal, hepatic, pancreatic, skin, prostate and bladder). Mantel–Haenszel odds ratios with 95% Confidence Intervals (MH‐OR, 95% CI) were calculated for all outcomes. Results: A total of 27 trials fulfilled the inclusion criteria. Retrieved trials had enrolled 27 744 and 20 441 patients in SGLT‐2 inhibitor and comparator groups, respectively. No difference was observed in the incidence of all malignancies between patients allocated to SGLT‐2i and comparators (MH‐OR 0.98[0.77–1.24]). The incidence of bladder cancer, and of any other type of cancer, was not significantly increased by treatment with any SGLT‐2i. Conclusions: Available data from randomized trials do not suggest a detrimental effect of SGLT‐2is on the incidence of malignancies in general, or in bladder cancer in particular. [ABSTRACT FROM AUTHOR]

Aims: Sodium glucose co‐transport‐2 (SGLT‐2) inhibitors reduce tubular glucose reabsorption, producing a reduction of blood glucose without stimulating insulin release. The aim of this meta‐analysis was the systematic collection of available data from randomized trials, in order to establish the durability of the efficacy of SGLT‐2 inhibitors on glycaemic control and body mass index. Methods: A meta‐analysis was performed, including all trials with a duration of at least 12 weeks, comparing SGLT‐2 inhibitors with non‐SGLT‐2 inhibitor agents in type 2 diabetes. The principal outcome was the effect of SGLT‐2 inhibitors on hemoglobin A1c (HbA1c) at 12, 24, 52 and 104 weeks. Data on body mass index at the same time points were also collected. Results: Among 66 randomized trials, HbA1c reduction at 12, 24, 52 and 104 weeks was 0.63% (0.57; 0.68, 0.63% (0.57; 0.70), 0.66% (0.57; 0.74) and 0.60% (0.40; 0.81), respectively. SGLT‐2 inhibitors showed a greater efficacy than dipeptidyl‐peptidase‐4 inhibitors (DPP‐4i). Sulfonylureas appeared to be superior to SGLT‐2 inhibitors at 12 weeks, but not at 24 and 52 weeks; SGLT‐2 inhibitors produced a greater reduction in HbA1c than did sulfonylureas at 104 weeks. SGLT‐2 inhibitor‐induced weight loss in placebo‐controlled trials appeared to increase progressively with the duration of treatment. Conclusions: SGLT‐2 inhibitors showed a good persistence of efficacy, at least up to 2 years, with a small but significant superiority over DPP‐4i. Sulfonylureas are more effective in the very short term, but less effective in the longer term. [ABSTRACT FROM AUTHOR]

Aims: Results with GLP1-receptor agonists (GLP-1RA) on microvascular complications of diabetes are contrasting. In trials designed for cardiovascular outcomes, both liraglutide and semaglutide were associated with a relevant reduction in the incidence and progression of nephropathy. On the other hand, in the same trials, semaglutide was associated with an increased progression of retinopathy, and a similar trend was observed for liraglutide. This meta-analysis is aimed at assessing the effects of GLP-1RA on retinopathy and nephropathy. Methods: A Medline search for GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, or semaglutide) was performed, collecting all randomized clinical trials with a duration >11 weeks, enrolling patients with type 2 diabetes, and comparing a GLP-1 receptor agonist with placebo or any other non-GLP-1 receptor agonist drug. Results: Of the 113 trials fulfilling the inclusion criteria, 78 and 62 did not report information on retinopathy and nephropathy, respectively. Treatment with GLP1-RA was not associated with a significant increase in the incidence of retinopathy (MH-OR [95% CI] 0.92 [0.74-1.16]. p = 0.49). In subgroup analyses, GLP1-RA were associated with a lower risk of retinopathy in comparison with sulfonylureas. Cases of macular edema were reported only in nine trials with no sign of increased risk. GLP1-RA reduced the incidence of nephropathy with respect to comparators (MH-OR [95% CI] 0.74 [0.60-0.92]. p = 0.005). This difference was significant versus placebo, but not versus any class of active comparators. Conclusions: GLP1-RA appear to reduce the incidence and/or progression of nephropathy and to have no specific effect on retinopathy-with the notable exception of semaglutide, which could have a negative impact on the retina. [ABSTRACT FROM AUTHOR]

Aims: Diabetic ketoacidosis (DKA) associated with SGLT-2 inhibitors (SGLT-2i) is a possible adverse event. In fact, SGLT-2i are capable of stimulating the release of glucagon and ketone re-absorption in the renal tubuli, thus increasing the concentration of ketone bodies.Methods: A Medline search for SGLT2i (dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, ertugliflozin, luseogliflozin) was performed, collecting all randomized trials with a duration of treatment≥12weeks, enrolling patients with type 2 diabetes, and comparing a SGLT2i with placebo or other comparators. The principal outcome was the effect of SGLT2i on ketoacidosis as serious adverse event.Results: Out of 72 trials reporting information on DKA, 9 reported at least one event of ketoacidosis; those eight trials enrolled 10,157 and 5396 in SGLT-2 inhibitors and comparator groups, respectively. No signal of increased risk for ketoacidosis was observed for SGLT2 inhibitors as a class (MH-OR [95% CI] 1.14 [0.45-2.88], p=0.78) or as individual molecule. The sensitivity analysis with continuity correction (inputing one event each in drug and comparator arms of each trial with zero events) suggested a reduced incidence of ketoacidosis in patients treated with SGLT-2 inhibitors (MH-OR 0.65 [0.47-0.90]; p=0.01).Conclusions: The results of clinical trials summarized in the present meta-analysis reassure us that, when the drug is properly prescribed, the risk of DKA is negligible. [ABSTRACT FROM AUTHOR]

The article presents the study on the measurement of hemoglobin A1c (HbA1c) variation through HbA1c or glycated albumin (GA) measurement for the prediction of the treatment response among type 2 diabetes patients. The high performance liquid chromatography (HPLC) method was used to measure HbA1c. The results were enumerated and conclude the values of GA and HbA1c and the correlation of HbA1c on short- and long-term glycemia.

In the manuscript, the events of nephropathy and retinopathy recorded for the LEADER trial (Marso et al. 2016) were erroneously imputed; the numbers reported in Table 1 for that trial refer to serious adverse events, and not to total events, as stated in Methods. The correct figures are 268 and 416 cases of nephropathy, and 106 and 92 cases of retinopathy in liraglutide and control arms, respectively. As a consequence, the overall risk (MH-OR [95% CI]) of nephropathy and retinopathy with GLP-1RA (vs all comparators) is 0.77 [0.67-0.88], p < 0.001, and 0.99 [0.80-1.21], p = 0.90, respectively. The analyses reported in Figs. 1 and 2 were also corrected and reported below, together with supplementary figures 3 and 5. Please note that liraglutide is associated with a significant reduction in the incidence of nephropathy, whereas for retinopathy the difference from placebo is no longer statistically significant. [ABSTRACT FROM AUTHOR]

Glucagon-Like Peptide-1 Receptor Agonists (GLP1-RA) has been associated with cholelithiasis in a previous meta-analysis. The publication of new trials suggests the need for an update. We collected trials with GLP1-RA vs. other therapies, calculating Mantel-Haenszel odds ratio (MH-OR, 95%CI). GLP1-RA significantly increased the risk of cholelithiasis (MH-OR 1.28 [1.11, 1.48]). [ABSTRACT FROM AUTHOR]

Aim Glucagon-like peptide 1 receptor agonists ( GLP1-RA) have been associated with an increased risk of pancreatitis and pancreatic cancer. Prior meta-analyses of randomized controlled trials failed to show any significant increase of risk; however, those meta-analyses did not include the recently published cardiovascular outcome trials ( CVOT) with GLP1-RA, which provide a substantial additional body of data. The aim of the present meta-analysis is to assess the effect of GLP1-RA on pancreatitis, pancreatic cancers and cholelithiasis. Materials and methods A Medline search for GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide or semaglutide) was performed, collecting all randomized clinical trials with a duration >11 weeks, enrolling patients with type 2 diabetes and comparing a GLP-1 receptor agonist with placebo or any other non- GLP-1 receptor agonist drug. Results Of the 113 trials fulfilling inclusion criteria, 13 did not report information on pancreatitis, whereas 72 reported no events in all treatment groups. The incidence of pancreatitis and pancreatic cancer with GLP1-RA was not significantly different from that observed in comparator arms ( MH-OR [95% CI] 0.93 [0.65-1.34], P = .71, and 0.94 [0.52-1.70], P = .84, respectively), whereas, a significantly increased risk of cholelithiasis ( MH-OR [95% CI] 1.30 [1.01-1.68], P = .041) was detected. Conclusions Presently available data confirm the safety of GLP-1 receptor agonists for pancreatitis. Conversely, therapy with those drugs is associated with an increased risk of cholelithiasis, which deserves further investigation. [ABSTRACT FROM AUTHOR]

Aim: To conduct a meta‐analysis of cardiovascular outcome trials on the effects of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) on major adverse cardiovascular events (MACE). Methods: A search of MEDLINE, EMBASE, Cochrane database and clinicaltrials.gov was performed to identify controlled trials (up to 15 June 2019) of GLP‐1RAs with a cardiovascular endpoint. The principal endpoint of the present meta‐analysis was MACE; secondary endpoints included myocardial infarction, stroke, cardiovascular and all‐cause mortality, and hospitalization for heart failure. Mantel–Haenszel odds ratios (MH‐ORs) with 95% confidence intervals (CIs) were calculated for all outcomes. Results: In the seven trials included, all placebo‐controlled, GLP‐1RA treatment was associated with a reduction in MACE (MH‐OR 0.87 [95% CI 0.81, 0.93]). Cardiovascular and all‐cause mortality, myocardial infarction and stroke were also reduced (MH‐OR 0.88 [95% CI 0.80, 0.96], MH‐OR 0.90 [95% CI 0.82, 0.98], MH‐OR 0.91 [95% CI 0.84, 0.98] and MH‐OR 0.86 [95% CI 0.77, 0.97], respectively). Results for hospitalization for heart failure were not statistically significant (MH‐OR 0.93 [95% CI 0.83, 1.04]). The meta‐analyses of patient subgroups showed a significant reduction in MACE with GLP‐1RAs, irrespective of gender, advanced age and obesity. Conclusions: GLP‐1RAs are associated with a reduction in cardiovascular morbidity and mortality in high‐risk patients with diabetes. This effect does not appear to be moderated by gender or body mass index. The possibility of different effects of GLP‐1RAs between patients in primary and secondary prevention merits further investigation. [ABSTRACT FROM AUTHOR]

Background: Concerns have been raised on the risk of lower limb amputations with SGLT-2 inhibitors. Aim of the present metanalysis is the assessment of the effect of SGLT-2inhibitors on peripheral artery disease and lower limb amputations in randomized controlled trials performed in patients with type 2 diabetes.Methods: A Medline and Embase search for "Canaglifozin" OR "Dapaglifozin" OR "Empaglifozin" OR "Ertuglifozin" OR "Ipraglifozin" OR Tofoglifozin" OR "Luseoglifozin" was performed, collecting randomized clinical trials (duration > 12 weeks) up to December 1st, 2018, comparing SGLT-2i at approved dose with placebo or other active comparators different from SGLT-2 inhibitors. Furthermore, unpublished studies were searched in the www.clinicaltrials.gov register. Separate analyses were performed for individual molecules of the class. In addition, a separate analysis was performed for placebo-controlled trials. Mantel-Haenszel odds ratio with 95% Confidence Interval (MH-OR) was calculated for all outcomes defined above.Results: A total of 27 trials fulfilling the inclusion criteria was identified. The overall incidence of peripheral artery disease was increased with SGLT-2 inhibitors (MH-OR: 1.26 [1.04, 1.52]). The increase of risk was statistically significant only with canagliflozin. MH-OR for amputation in the three cardiovascular safety trials with SGLT-2 inhibitors was 1.22 [0.59-2.52].Conclusions: At present, there is no reason to believe that empagliflozin or dapagliflozin increase the risk of either peripheral artery disease of lower limb amputations. Canagliflozin could be associated with a specific risk, which needs to be further investigated. [ABSTRACT FROM AUTHOR]

Aims: The aim of the present meta-analysis is the identification of the characteristics of patients, which predict the efficacy on HbA1c of glucagon-like peptide-1 receptor agonists (GLP-1 RA). Methods: A Medline and Embase search for 'exenatide' OR 'liraglutide' OR 'albiglutide' OR 'dulaglutide' OR 'lixisenatide' was performed, collecting randomized clinical trials (duration > 12 weeks) up to September 2016, comparing GLP-1 RA at the maximal approved dose with placebo or active drugs. Furthermore, unpublished studies were searched in the register. For meta-analyses, the outcome considered were 24- and 52-week HbA1c. Separate analyses were performed, whenever possible, for subgroups of trials based on several inclusion criteria. In addition, meta-regression analyses were performed for comparisons for which 10 or more trails were available. Results: A total of 92 trials fulfilling the inclusion criteria were identified. In placebo-controlled trials ( n = 41), the 24-week mean reduction of HbA1c with GLP-1 RA was − 0.75 [− 0.87; − 0.63]%. Shorter-acting molecules appear to be more effective in patients with lower fasting glucose, whereas longer-acting agents in patients with higher fasting hyperglycaemia. Obesity and duration of diabetes do not seem to moderate the efficacy of GLP-1 RA, whereas in non-Caucasians and older patients liraglutide could be less effective. At 52 weeks, only 9 placebo-controlled trials were available for preventing any reliable analyses. Conclusions: Using a variety of approaches (meta-analyses of subgroup of trials, meta-regression, systematic review of subgroup analyses in individual trials, and meta-analyses of subgroups of patients), we identified some putative predictors of efficacy of GLP-1 RA, which deserve further investigation. [ABSTRACT FROM AUTHOR]

The article presents information on the lowering of risks involved in limb amputation with the use of type 2 diabetes drug canagliflozin. Details related to it include a table with the statistics of the drugs and their effects, leg and finger amputation being among the adverse effects of the drugs, and the use of diabetes 2 type drug Empagliflozin are presented.

Background: Immune checkpoint inhibitors (ICI) exert their therapeutic effect by modulating the immune system and potentiating antitumor immunity. ICI have been associated with several immune-related adverse events, such as diabetes. However, no formal metaanalysis with this respect has been conducted so far. Aim of the present metaanalysis of randomized trials is to assess the effects of ICI on incident diabetes and hyperglycemia.Methods: A MEDLINE, Scopus, ISI-WOS, and Cochrane database search was performed to identify trials, enrolling patients with any form of cancer, up to April 23rd, 2019 in which ICI have been compared either with placebo or active comparators. Data were extracted from published reports or, if not available, from clinicaltrials.gov. The principal endpoints were the incidence of diabetes and cases of hyperglycemia, reported as adverse events. Mantel-Haenszel Odds Ratio with 95% Confidence Interval (MH-OR) was calculated for all outcomes. The study has been registered on PROSPERO website (CDR133927).Findings: Out of 42 trials retrieved, 40 reported information on incident diabetes or hyperglycemia. No association of ICI with incident diabetes (MH-OR 1.27 [0.66, 2.43], p = 0.47) was observed; whereas there was a trend toward an increased risk of hyperglycemia (MH-OR 1.45 [0.99, 2.13], p = 0.060), which reached statistical significance in sensitivity analyses and when analyzing separately placebo-controlled trials (MH-OR 1.95 [1.10, 3.49], p = 0.020). I2 statistics did not suggest any relevant heterogeneity for all the principal analyses performed.Interpretation: ICI treatment is associated with an increased risk of hyperglycemia, and an increase in the risk of diabetes cannot be excluded. [ABSTRACT FROM AUTHOR]

Aim: Observational studies and metanalyses of randomized trials on Dipeptidyl Peptidase-4 inhibitors (DPP4i) reported discordant results on the risk of pancreatitis and pancreatic cancer with this class of drugs. Aim of the present meta-analysis is the assessment of the effect of DPP4i treatment on the incidence of pancreatitis and pancreatic cancer, collecting all available evidence from randomized controlled trials. Methods Data Sources: an extensive Medline, Embase and Cochrane Database search for sitagliptin or vildagliptin or omarigliptin or saxagliptin or alogliptin or trelagliptin or anagliptin or linagliptin or gemigliptin or evogliptin or teneligliptin was performed up to up to September 30th, 2019. All trials performed on type 2 diabetes, with duration ≥24 weeks, and comparing of DPP4i with placebo or active drugs were collected. The study has been registered on PROSPERO (#153344). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all outcomes defined above. Results A total of 165 eligible trials were identified. DPP-4 inhibitors were not associated with an increased risk of pancreatitis (MH-OR 1.13 [0.86, 1.47]) or pancreatic cancer (MH-OR 0.86 [0.60, 1.24]) with no significant differences across individual molecules of the class.Conclusions: available data do not support the hypothesis of an association of DPP4i treatment with pancreatitis. Present data do not suggest any association of DPP4i with pancreatic cancer, although they are insufficient to draw definitive conclusions. [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) decreased serum uric acid in type 2 diabetes. Hyperuricemia is associated with an increased risk of nephrolithiasis. The present meta-analysis, performed on trials with duration ≥52 weeks in comparison with placebo or active comparators, suggests no effects of SGLT-2i on the risk of nephrolithiasis. [ABSTRACT FROM AUTHOR]

Aim: Basal insulin and DPP4 inhibitors are both possible options in patients with type 2 diabetes failing to oral drugs. The identification of clinical predictors of success with either one of the two approaches could be of help in personalizing therapy. Methods: The retrospective study was performed on a consecutive series of patients with type 2 diabetes ( n = 1,002) failing to at least one oral agent, who had been prescribed either basal insulin or DPP4 inhibitors in the previous 2 years, with a duration of follow-up of at least 6 months. Clinical predictors of success after 6 months from the beginning of second-line treatment were identified in the cohort. Results: Among patients receiving a prescription of basal insulin, the proportion of therapeutic success at 6 months was 26.5 %. At multivariate analysis, a higher age and BMI, and a lower duration of diabetes were associated with success, as well as treatment with acarbose; conversely, a history of ischemic heart disease was associated with failure. Prescription of DPP4 inhibitors produced a therapeutic success in 24.8 % of cases. At multivariate analysis, success was associated with a lower baseline HbA1c and duration of diabetes, and a higher BMI and comorbidity; in addition, a lower success rate was found in women after adjusting for other confounders. Conclusions: The present data support the view that insulin treatment is preferable in patients with severe hyperglycemia, failing to one or more drugs, whereas DPP4 inhibitors appear to be more useful in those with comorbid conditions. [ABSTRACT FROM AUTHOR]

Background. Patient education is capable of reducing the risk for diabetic foot ulcers. However, specific education on foot ulcer prevention was either included in broader programs addressing different parts of diabetes care or provided with time- and resource-consuming curricula. The aim of the study is to assess the feasibility and efficacy of a brief educational program for the prevention of diabetic foot ulcers in high-risk patients. Methods. The study was performed on type 2 diabetic patients, randomized in a 1 : 1 ratio either to intervention or to control group. The principal endpoint was the incidence of foot ulcers. The intervention was a two-hour program provided to groups of 5–7 patients, including a 30-minute face-to-face lesson on risk factors for foot ulcers, and a 90-minute interactive session with practical exercises on behaviors for reducing risk. Results. The study was prematurely terminated due to a highly significant difference in outcome between the two treatment groups. The final sample was therefore composed of 121 patients. Six patients, all in the control group, developed ulcers during the 6-month follow-up (10% versus 0%, p=0.012). Conclusions. A brief, 2-hour, focused educational program is effective in preventing diabetic foot ulcers in high-risk patients. [ABSTRACT FROM AUTHOR]