GLUcose COntrol Safety & Efficacy in type 2 DIabetes, a systematic review and NETwork meta-analysis.

BACKGROUND: The last international consensus on the management of type 2 diabetes (T2D) recommends SGLT-2 inhibitors or GLP-1 agonists for patients with clinical cardiovascular (CV) disease; metformin remains the first-line glucose lowering medication. Last studies suggested beneficial effects of SGLT-2 inhibitors or GLP-1 agonists compared to DPP-4 inhibitors, in secondary CV prevention. Recently, a potential benefit of SGLT-2 inhibitors in primary CV prevention also has been suggested. However, no comparison of all the new and the old hypoglycemic drugs is available on CV outcomes. We aimed to compare the effects of old and new hypoglycemic drugs in T2D, on major adverse cardiovascular events (MACE) and mortality. METHODS AND FINDINGS: We conducted a systematic review and network meta-analysis of clinical trials. Randomized trials, blinded or not, assessing contemporary hypoglycemic drugs on mortality or MACE in patients with T2D, were searched for in Medline, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov. References screening and data extraction were done by multiple observers. Each drug was analyzed according to its therapeutic class. A random Bayesian network meta-analysis model was used. The primary outcomes were overall mortality, cardiovascular mortality, and MACE. Severe adverse events and severe hypoglycemia were also recorded. 175,966 patients in 34 trials from 1970 to 2018 were included. No trials evaluating glinides or alpha glucosidase inhibitors were found. 17 trials included a majority of patients with previous cardiovascular history, 16 trials a majority of patients without. Compared to control, SGLT-2 inhibitors were associated with a decreased risk of overall mortality (OR = 0.84 [95% CrI: 0.74; 0.95]), SGLT-2 inhibitors and GLP-1 agonists with a decreased risk of MACE (OR = 0.89 [95% CrI: 0.81; 0.98] and OR = 0.88 [95% CrI: 0.81; 0.95], respectively). Compared to DPP-4 inhibitors, SGLT-2 inhibitors were associated with a decreased risk of overall mortality (OR = 0.82 [95% CrI: 0.69; 0.98]), GLP-1 agonists with a decreased risk of MACE (OR = 0.88 [95% CrI: 0.79; 0.99]). Insulin was also associated with an increased risk of MACE compared to GLP-1 agonists (OR = 1.19 [95% CrI: 1.01; 1.42]). Insulin and sulfonylureas were associated with an increased risk of severe hypoglycemia. In the trials including a majority of patients without previous CV history, the comparisons of SGLT-2 inhibitors, metformin and control did not showed significant differences on primary outcomes. We limited our analysis at the therapeutic class level. CONCLUSIONS: SGLT-2 inhibitors and GLP-1 agonists have the most beneficial effects, especially in T2D patients with previous CV diseases. Direct comparisons of SGLT-2 inhibitors, GLP-1 agonists and metformin are needed, notably in primary CV prevention. TRIAL REGISTRATION: PROSPERO CRD42016043823.

Efficacy and safety of insulin in type 2 diabetes: meta-analysis of randomised controlled trials.

BACKGROUND: It is essential to anticipate and limit the social, economic and sanitary cost of type 2 diabetes (T2D), which is in constant progression worldwide. When blood glucose targets are not achieved with diet and lifestyle intervention, insulin is recommended whether or not the patient is already taking hypoglycaemic drugs. However, the benefit/risk balance of insulin remains controversial. Our aim was to determine the efficacy and safety of insulin vs. hypoglycaemic drugs or diet/placebo on clinically relevant endpoints. METHODS: A systematic literature review (Pubmed, Embase, Cochrane Library) including all randomised clinical trials (RCT) analysing insulin vs. hypoglycaemic drugs or diet/placebo, published between 1950 and 2013, was performed. We included all RCTs reporting effects on all-cause mortality, cardiovascular mortality, death by cancer, cardiovascular morbidity, microvascular complications and hypoglycaemia in adults ≥ 18 years with T2D. Two authors independently assessed trial eligibility and extracted the data. Internal validity of studies was analyzed according to the Cochrane Risk of Bias tool. Risk ratios (RR) with 95 % confidence intervals (95 % CI) were calculated, using the fixed effect model in first approach. The I(2) statistic assessed heterogeneity. In case of statistical heterogeneity, subgroup and sensitivity analyses then a random effect model were performed. The alpha threshold was 0.05. Primary outcomes were all-cause mortality and cardiovascular mortality. Secondary outcomes were non-fatal cardiovascular events, hypoglycaemic events, death from cancer, and macro- or microvascular complications. RESULTS: Twenty RCTs were included out of the 1632 initially identified studies. 18 599 patients were analysed: Insulin had no effect vs. hypoglycaemic drugs on all-cause mortality RR = 0.99 (95 % CI =0.92-1.06) and cardiovascular mortality RR = 0.99 (95 % CI =0.90-1.09), nor vs. diet/placebo RR = 0.92 (95 % CI = 0.80-1.07) and RR = 0.95 (95 % CI 0.77-1.18) respectively. No effect was found on secondary outcomes either. However, severe hypoglycaemia was more frequent with insulin compared to hypoglycaemic drugs RR = 1.70 (95 % CI = 1.51-1.91). CONCLUSIONS: There is no significant evidence of long term efficacy of insulin on any clinical outcome in T2D. However, there is a trend to clinically harmful adverse effects such as hypoglycaemia and weight gain. The only benefit could be limited to reducing short term hyperglycemia. This needs to be confirmed with further studies.

Is there excess mortality in women screened with mammography: a meta-analysis of non-breast cancer mortality.

BACKGROUND: The objective of our meta-analysis and systematic review was to analyze non-breast cancer mortality in women screened with mammography versus non-screened women to determine whether there is excess mortality caused by screening. METHODS: We searched PubMed and the Web of Science up to 30 November 2010. We included randomized controlled trials with non-breast cancer mortality as the main endpoint. Two authors independently assessed trial quality and extracted data. RESULTS: There was no significant difference between groups at 13-year follow-up (odds ratio = 1.00 (95% CI 0.98 to 1.03) with average heterogeneity I2 = 61%) regardless of the age and the methodological quality of the included studies. The meta-analysis did not reveal excess non-breast cancer mortality caused by screening. If screening does have an effect on excess mortality, it is possible to provide an estimate of its maximum value through the upper confidence interval in good-quality methodological studies: up to 3% in the screened women group (12 deaths per 100,000 women). CONCLUSIONS: The all-cause death rate was not significantly reduced by screening when compared to the rate observed in unscreened women. However, mammography screening does not seem to induce excess mortality. These findings improve information given to patients. Finding more comprehensive data is now going to be difficult given the complexity of the studies. Individual modeling should be used because the studies fail to include all the aspects of a complex situation. The risk/benefit analysis of screening needs to be regularly and independently reassessed.

Are concomitant treatments confounding factors in randomized controlled trials on intensive blood-glucose control in type 2 diabetes? a systematic review.

BACKGROUND: Open-label, randomized controlled trials (RCTs) are subject to observer bias. If patient management is conducted without blinding, a difference between groups may be explained by other factors than study treatment. One factor may come from taking concomitant treatments with an efficacy on the studied outcomes. In type 2 diabetes, some antihypertensive or lipid-lowering drugs are effective against diabetic complications. We wanted to determine if these concomitant treatments were correctly reported in articles of RCTs on type 2 diabetes and if they might have influenced the outcome. METHODS: We performed a systematic review using Medline, Embase, and the Cochrane Library (from January 1950 to July 2010). Open-label RCTs assessing the effectiveness of intensive blood-glucose control in type 2 diabetes were included. We chose five therapeutic classes with proven efficacy against diabetes complications: angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor antagonists (AIIRAs), fibrates, statins, and aspirin. Differences between concomitant treatments were considered statistically significant when p < 0.05. RESULTS: A total of eight open-label RCTs were included, but only three (37.5%) of them published concomitant treatments. In two studies (ACCORD and ADVANCE), a statistically significant difference was observed between the two groups for aspirin (p = 0.02) and ACEIs (p = 0.02). CONCLUSIONS: Few concomitant treatments were published in this sample of open-label RCTs. We cannot completely eliminate an observer bias for these studies. This bias probably influenced the results to an extent that has yet to be determined.

Physicians' knowledge and practice of lung cancer screening: a cross-sectional survey comparing general practitioners, thoracic oncologists, and pulmonologists in France.

BACKGROUND: Screening for lung cancer by low-dose computed tomography scan (LDCTS) has been demonstrated to reduce lung cancer-specific and overall mortality rates in high-risk individuals. From trial to clinical practice, it is crucial to obtain an accurate level of knowledge of the physicians who will recruit patients for a screening program. The actual current practice and knowledge of practitioners are unknown. This could be critical to develop dedicated continuous medical education programs. MATERIALS AND METHODS: Three groups of French physicians--pulmonologists (PUs), thoracic oncologists (TOs), and general practitioners (GPs)--were surveyed through a dedicated questionnaire on lung cancer screening. RESULTS: A total of 242 physicians answered the questionnaire; 81% of TOs knew that LDCTS showed efficacy for screening lung cancer compared with 52% of PUs and 18% of GPs (P < .0001). Approximately one third of physicians recommended lung cancer screening in daily practice at the time of the survey, including 53% of PUs, 34% of TOs, and 20% of GPs (P < .001). However, 94% of GPs, 44% of PUs, and 33% of TOs used inappropriate tests, mainly chest radiography. Most GPs proposed screening for all smokers, whereas PUs and TOs reserved screening for heavy smokers (P = .040). Most PUs and TOs recommended annual LDCTS (76%), whereas the majority of GPs sent patients for screening tests every 3 to 5 years (93%; P < .0001). CONCLUSIONS: These results highlight the interest of physicians for lung cancer screening; meanwhile, our data stress the need for appropriate medical education and recommendations based on available evidence.

The IDEAL study : towards personalized drug treatment of hypertension.

OBJECTIVE: To identify markers (phenotypic, genetic, or environmental) of blood pressure (BP) response profiles to angiotensin converting enzyme inhibitors (ACEIs) and diuretics. METHODS: IDEAL was a crossover (two active and two wash out phases), double-blind, placebo-controlled trial. Eligible patients were untreated hypertensive, aged 25 to 70. After two visits, patients were randomized to one of four sequences. The main outcome was BP differences between the active treatment and placebo. RESULTS: One hundred and twenty-four patients were randomised: mean age 53, men 65%, family history of hypertension 60%. Average BP fall at each visit before randomisation was about 2% of the initial level reflecting both a regression to the mean and a placebo effect. CONCLUSION: The results are expected to improve knowledge in drug's mechanisms of action and pathophysiology of hypertension, and to help in personalizing treatment. The estimation of BP responses to each drug in standardized conditions provided a benefit to each participant.

Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials.

OBJECTIVE: To determine all cause mortality and deaths from cardiovascular events related to intensive glucose lowering treatment in people with type 2 diabetes. DESIGN: Meta-analysis of randomised controlled trials. DATA SOURCES: Medline, Embase, and the Cochrane database of systematic reviews. STUDY SELECTION: Randomised controlled trials that assessed the effect of intensive glucose lowering treatment on cardiovascular events and microvascular complications in adults (≥ 18 years) with type 2 diabetes. DATA EXTRACTION: Primary end points were all cause mortality and death from cardiovascular causes. Secondary end points were severe hypoglycaemia and macrovascular and microvascular events. Synthesis of results Results are reported as risk ratios with 99% confidence intervals. Statistical heterogeneity between trials was assessed with χ(2), τ(2), and I(2) statistics. A fixed effect model was used to assess the effect on the outcomes of intensive glucose lowering versus standard treatment. The quality of clinical trials was assessed by the Jadad score. RESULTS: 13 studies were included. Of 34,533 patients, 18,315 received intensive glucose lowering treatment and 16,218 standard treatment. Intensive treatment did not significantly affect all cause mortality (risk ratio 1.04, 99% confidence interval 0.91 to 1.19) or cardiovascular death (1.11, 0.86 to 1.43). Intensive therapy was, however, associated with reductions in the risk of non-fatal myocardial infarction (0.85, 0.74 to 0.96, P<0.001), and microalbuminuria (0.90, 0.85 to 0.96, P<0.001) but a more than twofold increase in the risk of severe hypoglycaemia (2.33, 21.62 to 3.36, P<0.001). Over a treatment period of five years, 117 to 150 patients would need to be treated to avoid one myocardial infarction and 32 to 142 patients to avoid one episode of microalbuminuria, whereas one severe episode of hypoglycaemia would occur for every 15 to 52 patients. In analysis restricted to high quality studies (Jadad score >3), intensive treatment was not associated with any significant risk of reductions but resulted in a 47% increase in risk of congestive heart failure (P<0.001). CONCLUSIONS: The overall results of this meta-analysis show limited benefits of intensive glucose lowering treatment on all cause mortality and deaths from cardiovascular causes. We cannot exclude a 9% reduction or a 19% increase in all cause mortality and a 14% reduction or a 43% increase in cardiovascular death. The benefit:risk ratio of intensive glucose lowering treatment in the prevention of macrovascular and microvascular events remains uncertain. The harm associated with severe hypoglycaemia might counterbalance the potential benefit of intensive glucose lowering treatment. More double blind randomised controlled trials are needed to establish the best therapeutic approach in people with type 2 diabetes.

Patient versus general practitioner perception of problems with treatment adherence in type 2 diabetes: from adherence to concordance.

OBJECTIVES: To determine the prevalence of problems with treatment adherence among type-2 diabetic patients with regards to medication, dietary advice, and physical activity; to identify the associated clinical and psychosocial factors; and to investigate the degree of agreement between patient-perceived and GP-perceived adherence. METHODS: Consecutive patients were solicited during visits to 39 GPs. In total, 521 patients self-reported on treatment adherence, anxiety and depression, and disease perception. The GPs reported clinical and laboratory data and patients' adherence. A multivariate analysis identified the factors associated with adherence problems. RESULTS: Problems of adherence to medication, dietary advice, and physical activity recommendations were reported by 17%, 62%, and 47% of the patients, respectively. Six independent factors were found associated with adherence problems: young age, body-mass index (BMI) > 30 kg/m(2), glycosylated haemoglobin (HbA(1c)) > 8%, single life, depression, and perception of medication as a constraint. Agreement between patients' and GPs' assessments of treatment problems reached 70%. CONCLUSION: In type 2 diabetes, problems with dietary advice or physical activity are far more frequent than problems with medication, and not all physicians are fully aware of patients' problems. More active listening and shared decision-making should enhance adherence and improve outcomes.

[Cervical smears among women after 65 years. One-year retrospective descriptive study]. / Frottis du col de l'utérus chez les femmes de plus de 65 ans. Etude descriptive rétrospective réalisée sur une année.

BACKGROUND: The recommendations of the French consensus (Lille 1990) advise the stop of the tracking by cervical smears of cancer at 65-years-old, if the former follow-up were regular and if the last two smears were normal. 33% cervical cancers are after 65-years-old. AIM: How many pathological smears are after 65 years? METHOD: Descriptive, retrospective study analyzing the results of 12339 smears of women of more than 65 years, carried out during one year in the same laboratory of anatomo-pathology. They were analysed with Bethesda's system. RESULTS: 2.67% of smears are of insufficient quality (CI 95%: 2, 46%; 3%); 2.43% of smears are pathological (CI 95%: 2, 2%; 2, 7%). That pathological smear's rate is comparable to the one found among women of less than 65-years-old (2 to 3%). The squamous cell carcinoma's rate is more important in this group. CONCLUSION: This work encourages us to continue smear's practice among women of more than 65 years.