Glycemic control and cancer outcomes in oncologic patients with diabetes: an Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), Italian Society of Pharmacology (SIF) multidisciplinary critical view.

BACKGROUND:  Increasing evidence suggests that diabetes increases the risk of developing different types of cancer. Hyperinsulinemia, hyperglycemia and chronic inflammation, characteristic of diabetes, could represent possible mechanisms involved in cancer development in diabetic patients. At the same time, cancer increases the risk of developing new-onset diabetes, mainly caused by the use of specific anticancer therapies. Of note, diabetes has been associated with a ∼10% increase in mortality for all cancers in comparison with subjects who did not have diabetes. Diabetes is associated with a worse prognosis in patients with cancer, and more recent findings suggest a key role for poor glycemic control in this regard. Nevertheless, the association between glycemic control and cancer outcomes in oncologic patients with diabetes remains unsettled and poorly debated. PURPOSE:  The current review seeks to summarize the available evidence on the effect of glycemic control on cancer outcomes, as well as on the possibility that timely treatment of hyperglycemia and improved glycemic control in patients with cancer and diabetes may favorably affect cancer outcomes.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

A meta-analysis of the hypoglycaemic risk in randomized controlled trials with sulphonylureas in patients with type 2 diabetes.

AIM: To assess hypoglycaemic risk with sulphonylureas in comparison with other drugs in randomized controlled trials. METHODS: Randomized trials with a duration ≥ 24 weeks, enrolling patients with type 2 diabetes, comparing sulphonylureas with placebo or active drugs different from other sulphonylureas. The principal outcome was the effect of sulphonylureas on the incidence of any or severe hypoglycaemia. Cumulative incidence of hypoglycaemia was estimated combining sulphonylurea groups of different trials with a random effect model and used for meta-regression analyses. RESULTS: The incidence of severe hypoglycaemia in patients treated with sulphonylureas was 1.2 [1.0-1.6]%. The overall risk of severe hypoglycaemia was increased more than threefold with sulphonylureas than with comparators. The proportion of patients with at least one hypoglycaemia while on sulphonylureas was 17.4 [14.5-20.8]%. The overall risk (Mantel-Haenszel Odds Ratio) of any hypoglycaemia with sulphonylureas versus comparators was 3.69 [3.47-3.93] (p < 0.001). Meta-regression analysis suggested that the incidence of any hypoglycaemia was higher in trials enrolling patients with higher body mass index (BMI) and lower haemoglobin A1c (HbA1c). CONCLUSIONS: In conclusion, hypoglycaemia, including severe hypoglycaemia, is frequent in patients treated with sulphonylureas, particularly when baseline HbA1c levels are lower and BMI levels higher. Further studies are needed to characterize predictors for the identification of patients at higher risk.

Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk: a meta-analysis of randomized clinical trials.

AIMS: New drugs for type 2 diabetes need to demonstrate their cardiovascular safety, due regulatory requirements from the Food and Drug Administration. For this reason, glucagon-like peptide-1 receptor agonists (GLP-1 RA) are currently undergoing large-scale, long-term randomized trials specifically designed for cardiovascular outcomes. Aim of the present meta-analysis of randomized clinical trials is the assessment of the effects of GLP-1 RA on major cardiovascular events (MACE), mortality and cardiovascular risk factors. METHODS: A meta-analysis was performed including all trials with a duration of at least 6 months, comparing a GLP-1 RA with a non-GLP-1 RA agent in type 2 diabetes. MACE and mortality were retrieved and combined to calculate Mantel-Haenzel odds ratio (MH-OR). Furthermore, data on endpoint systolic and diastolic blood pressure, total and high-density lipoprotein (HDL) cholesterol and triglyceride were collected. RESULTS: Of 37 selected trials, 33 reported information on MACE, and 25 reported at least one event. The difference in the incidence of MACE between GLP-1 RA and comparators did not reach statistical significance [MH-OR 0.78 (0.54-1.13), p = 0.18]. GLP-1 RA were associated with a significant reduction in the incidence of MACE in comparisons with placebo and pioglitazone, with a non-significant trend towards reduction in DPP4i-controlled studies. No significant effect of GLP-1 RA was observed on mortality, although a non-significant favourable trend was observed in comparisons with placebo. CONCLUSIONS: The present meta-analysis confirms the cardiovascular safety of GLP-1 RA, at least in the short term and in low-risk individuals. GLP-1 RA could have a beneficial effect on the incidence of MACE, at least in comparison with placebo.

Dipeptidyl peptidase-4 inhibitors and heart failure: a meta-analysis of randomized clinical trials.

BACKGROUND & AIMS: Recently, the SAVOR TIMI-53 (Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus--Thrombolysis in Myocardial Infarction-53) reported a significant increase in the risk of hospitalizations for heart failure in patients treated with saxagliptin in comparison with placebo. Aim of the present meta-analysis is the systematic collection and synthesis of information on treatment-emergent cases of acute heart failure described in randomized clinical trials with DPP4. DATA SOURCES: An extensive Medline, Embase, and Cochrane Database search for "vildagliptin", "sitagliptin", "saxagliptin", "alogliptin", "linagliptin", and "dutogliptin" was performed, collecting all randomized clinical trials on humans up to October 1st, 2013. Studies were included if they satisfied the following criteria: i) randomized trials, ii) duration ≥24 weeks; iii) on type 2 diabetes; iv) comparison of DPP4i with placebo or active drugs. The principal outcome was the effect of DPP4i on the incidence of acute heart failure. A total of 84 eligible trials was identified. The overall risk of acute heart failure was higher in patients treated with DPP4i in comparison with those treated with placebo/active comparators (MH-OR: 1.19[1.03; 1.37]; p = 0.015). When trials with non-cardiovascular outcomes were analysed separately no signal of risk was detectable. CONCLUSION: Available data from RCTs suggest that DPP4i could be associated with an increased risk of heart failure, without any clear evidence of differences among drugs of the class. Although it is plausible that the risk is greater in some sub-populations of patients, current evidence is not yet sufficient to identify susceptible patients.

Cardiovascular safety of sulfonylureas: a meta-analysis of randomized clinical trials.

AIM: Cardiovascular safety of sulfonylurea has been questioned by some authors. This article aims at collecting all available data on this issue from randomized trials. METHODS: A meta-analysis was performed including all trials with a duration of at least 6 months, comparing a sulfonylurea with a non-sulfonylurea agent in type 2 diabetes. Major cardiovascular events (MACE) and mortality were retrieved and combined to calculate Mantel-Haenzel odds ratio (MH-OR). RESULTS: Of the 115 selected trials, 62 reported information on MACE, and 30 reported at least one event. MH-OR for sulfonylurea was 1.08 [0.86-1.36], p = 0.52 (1.85 [1.20-2.87], p = 0.005, in the five trials vs. DPP4 inhibitors, no significant differences vs. other comparators). The MH-OR for myocardial infarction and stroke was 0.88 [0.75-1.04], p = 0.13 and 1.28 [1.03-1.60], p = 0.026, respectively. Mortality was significantly increased with sulfonylureas (MH-OR: 1.22 [1.01-1.49], p = 0.047). CONCLUSIONS: In type 2 diabetes, the use of sulfonylureas is associated with increased mortality and a higher risk of stroke, whereas the overall incidence of MACE appears to be unaffected. Significant differences in cardiovascular risk could be present in direct comparisons with specific classes of glucose-lowering agents, such as DPP4 inhibitors, but this hypothesis needs to be confirmed in long-term cardiovascular outcomes trials. The results of this meta-analysis need to be interpreted with caution, mainly because of limitations in trial quality and under-reporting of information on cardiovascular events and mortality. However, the cardiovascular safety of sulfonylureas cannot be considered established unless it is evaluated in long-term cardiovascular outcomes trials.

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

AIMS: Preliminary data from randomized trials with metabolic outcomes have shown that treatment with dipeptidyl peptidase-4 inhibitors (DPP4i) could be associated with a reduced incidence of major cardiovascular events (MACE). The present meta-analysis is aimed at verifying this protective effect, collecting all available data from randomized trials. METHODS: A comprehensive search for published and unpublished trials with a duration ≥24 weeks comparing DPP4i with placebo or other drugs was performed, retrieving all MACE reported as serious adverse events together with death from any cause. Mantel-Haenzel odds ratio (MH-OR) was calculated with random effect models for MACE, myocardial infarction, stroke and mortality. When available, effects on glycated haemoglobin, lipid profile and blood pressure were also assessed and used for the estimation of the modification of risk for myocardial infarction using the UKPDS risk engine. RESULTS: A total of 70 trials, enrolling 41 959 patients with a mean follow-up of 44.1 weeks, was collected and included in the analysis. The MH-OR (95% Confidence Interval) was 0.71[0.59;0.86], 0.64[0.44;0.94], 0.77[0.48;1.24] and 0.60[0.41;0.88] for MACE, myocardial infarction, stroke and mortality, respectively. CONCLUSIONS: Treatment with DPP4i reduces the risk of cardiovascular events (particularly myocardial infarction) and all-cause mortality in patients with type 2 diabetes. The reduction in the incidence of myocardial infarction is greater than what predicted on the basis of conventional risk factors, suggesting a role for other mechanisms.

Fasting and post-prandial glucose and diabetic complication. A meta-analysis.

BACKGROUND: The reduction of hemoglobin A1c (HbA1c) levels is recognized as a useful means of preventing diabetic complications. HbA1c results from both fasting and post-prandial glycemia, and therefore FPG and PPG could provide different, and independent, contributions to long-term outcomes. Aim of the present meta-analysis is the assessment of the effects of reduction of FPG and PPG on cardiovascular outcomes in randomized controlled trials. METHODS: An extensive search of Medline was performed for all randomized trials with a duration of at least 52 weeks and performed on glucose-lowering agents. Differences in the incidence of cardiovascular events, and all-cause and cardiovascular mortality were assessed in trials comparing different treatments with a between-group difference in FPG or PPG at endpoint greater than 1 mmol/l. RESULTS: The Mantel-Haenszel Odds Ratio (MH-OR) for cardiovascular events and all-cause and cardiovascular mortality in patients on more intensive treatments, in trials with a between-group difference of PPG greater than 1 mmol/l, was not significantly different from controls (MH-OR [95%CI] 0.90 [0.51-1.58] for MACE); on the contrary, more intensive treatment of FPG produced a significantly lower all-cause (MH-OR 0.90 [0.81-0.99], p = 0.03) and cardiovascular (MH-OR 0.86 [0.76-0.97], p = 0.012) mortality, with no significant effect on the incidence of major cardiovascular events. CONCLUSIONS: In conclusion, reduction of FPG is associated with reduced cardiovascular mortality. Data on PPG are still scarce, but they point in the same direction.