LDL-cholesterol target levels achievement in high-risk patients: An (un)expected gender bias.

BACKGROUND AND AIMS: Lowering low-density lipoprotein cholesterol (LDL-C) is the cornerstone of cardiovascular disease prevention. Collection of epidemiological data is crucial for monitoring healthcare appropriateness. This analysis aimed to evaluate the proportion of high-risk patients who achieved guidelines recommended LDL-C goal, and explore the predictors of therapeutic failure, with a focus on the role of gender. METHODS AND RESULTS: Health administrative and laboratory data from seven Local Health Districts in Tuscany were collected for residents aged ≥45 years with a history of major adverse cardiac or cerebrovascular event (MACCE) and/or type 2 diabetes mellitus (T2DM) from January 1, 2019, to January 1, 2021. The study aimed to assess the number of patients with optimal levels of LDL-C (<55 mg/dl for patients with MACCE and <70 mg/dl for patients with T2DM without MACCE). A cohort of 174 200 individuals (55% males) was analyzed and it was found that 11.6% of them achieved the target LDL-C levels. Female gender was identified as an independent predictor of LDL-C target underattainment in patients with MACCE with or without T2DM, after adjusting for age, cardiovascular risk factors, comorbidities, and district area (adjusted-IRR 0.58 ± 0.01; p < 0.001). This result was consistent in subjects without lipid-lowering therapies (adjusted-IRR 0.56 ± 0.01; p < 0.001). CONCLUSION: In an unselected cohort of high-risk individuals, females have a significantly lower probability of reaching LDL-C recommended targets. These results emphasize the need for action to implement education for clinicians and patients and to establish clinical care pathways for high-risk patients, with a special focus on women.

Pancreatitis and pancreatic cancer in patients with type 2 diabetes treated with glucagon-like peptide-1 receptor agonists: an updated meta-analysis of randomized controlled trials.

INTRODUCTION: An association between glucagon-like peptide-1 receptor agonists (GLP1-RA) and risk of pancreatitis and pancreatic cancer has been suggested. Since its first description, several new trials (including three cardiovascular outcome trials) have been published, substantially increasing the available data set. This suggests the need for an update of the previous meta-analysis. EVIDENCE ACQUISITION: A Medline search for GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, or semaglutide) was performed, collecting all randomized clinical trials, with duration ≥52 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. The endpoints were pancreatitis, pancreatic cancer reported as serious adverse events. Mantel-Haenszel Odds Ratio (MH-OR) with 95% confidence interval (95% CI) was calculated for all outcomes defined above, on an intention-to-treat basis. EVIDENCE SYNTHESIS: A total of 43 trials fulfilling inclusion criteria (all reporting data on pancreatitis and pancreatic cancer) was identified. GLP-1 RA showed no association with pancreatitis (MH-OR 1.24 [0.94, 1.64]; P=0.13) and pancreatic cancer (MH-OR 1.28 [0.87, 1.89]; P=0.20). CONCLUSIONS: No clear evidence of risk for pancreatitis was observed, whereas data on pancreatic cancer are too scarce to draw any conclusion.

Covid-19 pandemic, diabetes and glycemic control: Results of a retrospective cohort study of 230.000 persons with diabetes in tuscany.

BACKGROUND AND AIMS: The COVID-19 pandemic affected the processes of routine care for chronic patients due to disrupted delivery care. The aim of the present study is to verify the COVID-19 pandemic effects on diabetes control and management. METHODS AND RESULTS: The study was designed as a retrospective observational study, performed on two cohorts of patients with diabetes in 2019 and 2020. Data used for the analyses were gathered from administrative and laboratory databases, which do not include any sensible information on COVID-19. The Tuscany Regional Health Agency is data controller for current administrative databases and has been working to produce available information for policy decision-making. In 2020, in comparison with 2019, a relevant reduction of the number of patients measuring HbA1c was observed during the March-April lockdown, and again during the second pandemic wave in Autumn. A similar pattern was observed for specialist visits for diabetes, for which the introduction of televisits only partly compensated for the reduction of traditional office visits. The number of patients receiving drugs for diabetes each week in 2020 was very similar to 2019. The mean HbA1c values and the proportion of HbA1c values > 8% for each week, were higher during the 2020 Spring and Autumn lockdown. CONCLUSION: COVID-19 pandemic negatively impacts diabetes management, reducing specialist visits and HbA1c determinations during the first and second pandemic wave. Despite a satisfactory continuity in pharmacological treatment, short-term impairment of average glycemic control was detected, particularly in Autumn.

Major Amputation In Non-Healing Ulcers: Outcomes and Economic Issues. Data from a Cohort of Patients with Diabetic Foot Ulcers.

Background: Foot ulcers have a relevant economic impact on Health Care Systems and the cost-effectivenesseffectiveness of options is not clear. The aim of this study was the assessment of costs for ulcers treatment after 6, 12, and 18 months of follow-up, compared to those for major amputation. Methods: A retrospective study was carried out on 196 types 2 diabetic patients with foot ulcers. The principal endpoints were 1) the proportion of recovered patients among those with ulcers not healed after 6 and 12 months; 2) the assessment of direct costs for treatment of ulcers 6, 12, and 18 months of follow-up, as compared to the cost of major amputation. The economic evaluation was performed considering the perspective of the local health system. Results: Out of 196 patients, 85(46.2%), 131(71.6%), and 140(85.9%) healed within 6, 12, and 18 months, respectively. The average health cost during the 18-month follow-up was 5402€ per patient. We calculated hypothetical costs for three different scenarios, in which patients who did not heal within 6 months underwent a major amputation at 6, 1,2, or 18 months. Costs for the standard of care for all these scenarios (6,094, 7,256, and 7649€ for 6, 12, or 18 months, respectively) were significantly lower than that for major amputations (21,065€). Conclusions: A conservative approach appears more convenient than major amputations in ulcers not healing after 6 months, irrespective of the estimated risk of individual patients.

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.

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.

Rate and Predictors of Hesitancy toward SARS-CoV-2 Vaccine among Type 2 Diabetic Patients: Results from an Italian Survey.

Vaccine hesitancy (VH) has been identified as one of the major health concerns of our time by the World Health Organization. It may prove especially detrimental in the light of the ongoing SARS-CoV-2 pandemic, as vaccination campaigns still represent the primary strategy against the detrimental consequences of the pandemic. Among patients suffering from type 2 diabetes mellitus (DB), who are particularly vulnerable to COVID-19, VH might represent an even more serious threat. Therefore, our study focuses on identifying potential determinants of VH among patients with type 2 diabetes. Study participants (n = 1176) filled in a two-section online self-administered questionnaire, answering questions regarding demographic and anamnestic data, as well as their intention to accept any vaccination against COVID-19. Some possible reasons underlying VH were investigated as well. An overall hesitancy rate of 14.2% was registered. Data showed how older age, male gender, higher education level, and having been vaccinated for seasonal influenza in 2020-2021 were associated with a significantly higher propensity to receive the COVID-19 vaccine. On the contrary, having experienced adverse effects following past vaccinations was a negative predictor. In addition to confirming an array of predictors of VH, we found a worryingly high prevalence of VH among diabetics, who have been shown to be particularly exposed to severe COVID-19 and death. These findings may be useful in planning targeted action toward acceptance improvement and enhancing the efficacy of vaccination campaigns.

Factors associated with increased all-cause mortality during the COVID-19 pandemic in Italy.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 (r2 = 0.61, p < 0.001) and total cases (r2 = 0.30, p = 0.012), and an inverse correlation with cases/total tests ratio (r2 = 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. CONCLUSIONS: 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.

Major cardiovascular events, heart failure, and atrial fibrillation in patients treated with glucagon-like peptide-1 receptor agonists: An updated meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Glucagon-like Peptide 1 Receptor Agonists (GLP1-RA) has been associated with a reduction of major cardiovascular events (MACE) and mortality on the basis of the results of cardiovascular outcome trials (CVOT). Several meta-analyses on this issue have been recently published; however, they were all restricted to CVOT, with the exclusion of all studies designed for other endpoints; moreover, other cardiovascular endpoints, such as atrial fibrillation and heart failure have not been fully explored. METHODS AND RESULTS: 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 ≥52 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. We included 43 trials, enrolling 63,134 patients. A significant reduction of MACE (MH-OR 0.87 [0.83, 0.92]), all-cause mortality (MH-OR 0.89 [0.83, 0.96]), and a nonstatistical trend toward reduction of heart failure (MH-OR 0.93 [0.85, 1.01]) was observed - GLP1-RA did not increase the risk of atrial fibrillation (MH-OR 0.94 [0.84, 1.04]). CONCLUSION: The present meta-analysis confirms the favorable effects of glucagon-like peptide-1 receptor agonists on major cardiovascular events, cardiovascular and all-cause mortality, stroke, and possibly myocardial infarction. Conversely, the effects on heart failure remain uncertain. Available data on atrial fibrillation seems to exclude any major safety issues in this respect. REGISTRATION NUMBER (PROSPERO): CRD42018115577.

Bullous pemphigoid and dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized controlled trials.

PURPOSE: An increasing body of evidence suggests that dipeptidyl-peptidase 4 (DPP-4) inhibitors could play a role in the development of bullous pemphigoid. The knowledge regarding this association is based on case reports, pharmacovigilance database analyses, and observational studies. Data from randomized clinical trials are a relevant source of information on adverse events. Since no single trial has a sufficient power to assess the risk of very rare adverse events, such as pemphigoid, metanalyses of RCTs could be a useful tool for exploring this issue. METHODS: An extensive Medline, Embase and Cochrane Database search for sitagliptin or vildagliptin, 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 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 pemphigoid. RESULTS: A total of 138 eligible trials were identified (61,514 patients in DPP-4 inhibitors and 59,661 patients in the control group). Only six trials reported at least one case of pemphigoid (17 and 1 cases in DPP4i and control groups, respectively). DPP-4 inhibitors were associated with an increased risk of pemphigoid (MH-OR 4.44 [1.31, 15.00], p = 0.020). A separate analysis for trials with linagliptin showed a significant increase of BP with the active drug (MH-OR 4.69 [1.09, 20.22]; p = 0.04). CONCLUSIONS: In conclusion, available data from randomized controlled trials seem to confirm the association between DPP-4 inhibitors and bullous pemphigoid. This association could be limited to one molecule of the class (i.e., linagliptin), although data on other DPP4-i (e.g., vildagliptin) are insufficient to rule out similar detrimental effects.

Immune checkpoints inhibitors and hyperglycemia: A Meta-analysis of randomized controlled trials.

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.

Cholelithiasis in patients treated with Glucagon-Like Peptide-1 Receptor: An updated meta-analysis of randomized controlled trials.

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]).

Risk of cancer in patients treated with dipeptidyl peptidase-4 inhibitors: an extensive meta-analysis of randomized controlled trials.

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.

Exploring the heterogeneity of the effects of SGLT-2 inhibitors in cardiovascular outcome trials.

BACKGROUND AND AIM: The interpretation of discrepancies across cardiovascular safety trials (CVOT) with SGLT-2 inhibitors in the incidence of major cardiovascular events (MACE) and mortality is complex, because of heterogeneity in trial protocols and baseline characteristics of patients enrolled. Aim of this analysis is the exploration of possible determinants of heterogeneity of relative risk reduction for major cardiovascular events (MACE) and all-cause mortality. METHODS AND RESULTS: Incidence of events (MACE and mortality) in intervention and control groups and baseline characteristics of patients were extracted for each trial (EMPAREG, CANVAS, and DECLARE). For studies including both primary and secondary prevention cohorts, those two subgroups were considered separately. Metaregression analysis was used to assess the association of relative risk reduction with baseline characteristics of patients, including observed incidence of events with placebo. The estimated reduction in the incidence of MACE associated with SGLT-2 inhibitors showed a significant association with the incidence of MACE in the control group, suggesting that a greater effect was observed in trials enrolling patients at higher risk (Slope -0.008 [-0.023; 0.007], p = 0.31). A higher proportion of patients treated with statins, ß-blockers and insulin at baseline was associated with a greater reduction of MACE, but not of mortality. CONCLUSIONS: In CVOT trials, the magnitude of the effect of SGLT-2 inhibitors on MACE is driven by absolute risk of enrolled patients; as a consequence, the estimated risk reduction is lower in primary prevention cohorts, which have a lower risk. This result supports the hypothesis of a class effect of SGLT-2 inhibitors on MACE.

Pancreatitis and pancreatic cancer in patientes treated with Dipeptidyl Peptidase-4 inhibitors: An extensive and updated meta-analysis of randomized controlled trials.

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.

Glucagon-like peptide-1 receptor agonists and cardiovascular outcomes in patients with and without prior cardiovascular events: An updated meta-analysis and subgroup analysis of randomized controlled trials.

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.

Nephrolithiasis and sodium-glucose co-transporter-2 (SGLT-2) inhibitors: A meta-analysis of randomized controlled trials.

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.

Peripheral artery disease and amputations with Sodium-Glucose co-Transporter-2 (SGLT-2) inhibitors: A meta-analysis of randomized controlled trials.

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.

Sodium-glucose co-transporter-2 (SGLT-2) inhibitors and cancer: A meta-analysis of randomized controlled trials.

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.

Short and medium-term efficacy of sodium glucose co-transporter-2 (SGLT-2) inhibitors: A meta-analysis of randomized clinical trials.

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.