Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors With All-Cause Mortality in Patients With Type 2 Diabetes

Question  How do sodium-glucose cotransporter 2 (SGLT-2) inhibitors, glucagon-like peptide 1 (GLP-1) agonists, and dipeptidyl peptidase 4 (DPP-4) inhibitors compare in reducing mortality and cardiovascular events in patients with type 2 diabetes?

Findings  In this network meta-analysis that includes 236 trials with 176 310 participants, the use of SGLT-2 inhibitors or GLP-1 agonists was significantly associated with lower all-cause mortality compared with the control groups (placebo or no treatment) (hazard ratio [HR], 0.80, and HR, 0.88, respectively) and with DPP-4 inhibitors (HR, 0.78, and HR, 0.86, respectively).

Meaning  In patients with type 2 diabetes, the use of SGLT-2 inhibitors or GLP-1 agonists was associated with better mortality outcomes than DPP-4 inhibitors.

Reference: JAMA. 2018;319(15):1580-1591.


Association Between Baseline LDL-C Level and Total and Cardiovascular Mortality After LDL-C Lowering

Question  Does the magnitude of reductions in total and cardiovascular mortality after low-density lipoprotein cholesterol (LDL-C) lowering depend on the baseline LDL-C level?

Findings  In this meta-analysis of 34 randomized clinical trials that included 270 288 participants, more intensive LDL-C–lowering therapy was associated with a progressive reduction in total mortality with higher baseline LDL-C levels (rate ratio, 0.91 for each 40-mg/dL increase in baseline level); however, this relationship was not present with baseline LDL-C levels less than 100 mg/dL. There was a similar relationship for cardiovascular mortality.

Meaning  The greatest benefit from LDL-C–lowering therapy may occur for patients with baseline LDL-C levels of 100 mg/dL or greater.

Reference: JAMA. 2018;319(15):1566-1579.

Association of Inhaled Corticosteroids and Long-Acting β-Agonists as Controller and Quick Relief Therapy With Exacerbations and Symptom Control in Persistent Asthma

Question  What is the efficacy associated with using inhaled corticosteroids and long-acting β-agonists (LABAs) together as both the controller and the quick relief therapy termed single maintenance and reliever therapy(SMART) in patients with persistent asthma?

Findings  In this meta-analysis that included 22 524 patients aged 12 years or older and 341 children aged 4 to 11 years with persistent asthma, SMART was associated with a significantly lower risk of asthma exacerbations compared with a higher dose of inhaled corticosteroids and LABA as controller therapy, absolute risk difference, −2.8% for the older age group and −12.0% for the younger age group, although less robust data were available for this group.

Meaning  SMART was associated with better clinical outcomes than conventional approaches in patients with persistent asthma.

Reference: JAMA. 2018;319(14):1485-1496.

Association of Inhaled Corticosteroids and Long-Acting Muscarinic Antagonists With Asthma Control in Patients With Uncontrolled, Persistent Asthma

Question  What is the efficacy associated with long-acting muscarinic antagonists (LAMAs) as add-on therapy to inhaled corticosteroids in patients with uncontrolled, persistent asthma?

Findings  In this meta-analysis that included 15 randomized clinical trials with 7122 participants 12 years or older with uncontrolled, persistent asthma, LAMA vs placebo as an add-on therapy to inhaled corticosteroids was associated with a lower risk of exacerbations requiring systemic corticosteroids (risk difference, −1.8).

Meaning  LAMA use was associated with better clinical outcomes than placebo in patients with uncontrolled, persistent asthma.

Reference: JAMA. 2018;319(14):1473-1484.

Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis


Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder.


We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies’ risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291.


We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89–2·41) for amitriptyline and 1·37 (1·16–1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72–0·97) and fluoxetine (0·88, 0·80–0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01–1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19–1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51–0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43–0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30–2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low.


All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants.


National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science.

Reference: The Lancet, Volume 391, No. 10128, p1357–1366, 7 April 2018

Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults

Question  Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?

Findings  In this meta-analysis of 33 randomized clinical trials that included 51 145 participants, the use of supplements that included calcium, vitamin D, or both was not associated with a significant difference in the risk of hip fractures compared with placebo or no treatment (risk ratio, 1.53, 1.21, and 1.09, respectively).

Meaning  These findings do not support the routine use of these supplements in community-dwelling older adults.

Reference: JAMA. 2017;318(24):2466-2482.

Coffee consumption and health

Objectives To evaluate the existing evidence for associations between coffee consumption and multiple health outcomes.

Design Umbrella review of the evidence across meta-analyses of observational and interventional studies of coffee consumption and any health outcome.

Data sources PubMed, Embase, CINAHL, Cochrane Database of Systematic Reviews, and screening of references.

Eligibility criteria for selecting studies Meta-analyses of both observational and interventional studies that examined the associations between coffee consumption and any health outcome in any adult population in all countries and all settings. Studies of genetic polymorphisms for coffee metabolism were excluded.

Results The umbrella review identified 201 meta-analyses of observational research with 67 unique health outcomes and 17 meta-analyses of interventional research with nine unique outcomes. Coffee consumption was more often associated with benefit than harm for a range of health outcomes across exposures including high versus low, any versus none, and one extra cup a day. There was evidence of a non-linear association between consumption and some outcomes, with summary estimates indicating largest relative risk reduction at intakes of three to four cups a day versus none, including all cause mortality (relative risk 0.83, 95% confidence interval 0.83 to 0.88), cardiovascular mortality (0.81, 0.72 to 0.90), and cardiovascular disease (0.85, 0.80 to 0.90). High versus low consumption was associated with an 18% lower risk of incident cancer (0.82, 0.74 to 0.89). Consumption was also associated with a lower risk of several specific cancers and neurological, metabolic, and liver conditions. Harmful associations were largely nullified by adequate adjustment for smoking, except in pregnancy, where high versus low/no consumption was associated with low birth weight (odds ratio 1.31, 95% confidence interval 1.03 to 1.67), preterm birth in the first (1.22, 1.00 to 1.49) and second (1.12, 1.02 to 1.22) trimester, and pregnancy loss (1.46, 1.06 to 1.99). There was also an association between coffee drinking and risk of fracture in women but not in men.

Conclusion Coffee consumption seems generally safe within usual levels of intake, with summary estimates indicating largest risk reduction for various health outcomes at three to four cups a day, and more likely to benefit health than harm. Robust randomised controlled trials are needed to understand whether the observed associations are causal. Importantly, outside of pregnancy, existing evidence suggests that coffee could be tested as an intervention without significant risk of causing harm. Women at increased risk of fracture should possibly be excluded.

Reference:  BMJ 2017;359:j5024