Lise Lotte Gluud

Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study

Objective To examine whether the association of inadequate or unclear allocation concealment and lack of blinding with biased estimates of intervention effects varies with the nature of the intervention or outcome. Design Combined analysis of data from three meta-epidemiological studies based on collections of meta-analyses. Data sources 146 meta-analyses including 1346 trials examining a wide range of interventions and outcomes. Main outcome measures Ratios of odds ratios quantifying the degree of bias associated with inadequate or unclear allocation concealment, and lack of blinding, for trials with different types of intervention and outcome. A ratio of odds ratios <1 implies that inadequately concealed or non-blinded trials exaggerate intervention effect estimates. Results In trials with subjective outcomes effect estimates were exaggerated when there was inadequate or unclear allocation concealment (ratio of odds ratios 0.69 (95% CI 0.59 to 0.82)) or lack of blinding (0.75 (0.61 to 0.93)). In contrast, there was little evidence of bias in trials with objective outcomes: ratios of odds ratios 0.91 (0.80 to 1.03) for inadequate or unclear allocation concealment and 1.01 (0.92 to 1.10) for lack of blinding. There was little evidence for a difference between trials of drug and non-drug interventions. Except for trials with all cause mortality as the outcome, the magnitude of bias varied between meta-analyses. Conclusions The average bias associated with defects in the conduct of randomised trials varies with the type of outcome. Systematic reviewers should routinely assess the risk of bias in the results of trials, and should report meta-analyses restricted to trials at low risk of bias either as the primary analysis or in conjunction with less restrictive analyses.

Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials

Objective To determine whether treatment with agonists of glucagon-like peptide-1 receptor (GLP-1R) result in weight loss in overweight or obese patients with or without type 2 diabetes mellitus. Design Systematic review with meta-analyses. Data sources Electronic searches (Cochrane Library, Medline, Embase, and Web of Science) and manual searches (up to May 2011). Review methods Randomised controlled trials of adult participants with a body mass index of 25 or higher; with or without type 2 diabetes mellitus; and who received exenatide twice daily, exenatide once weekly, or liraglutide once daily at clinically relevant doses for at least 20 weeks. Control interventions assessed were placebo, oral antidiabetic drugs, or insulin. Data extraction Three authors independently extracted data. We used random effects models for the primary meta-analyses. We also did subgroup, sensitivity, regression, and sequential analyses to evaluate sources of intertrial heterogeneity, bias, and the robustness of results after adjusting for multiple testing and random errors. Results 25 trials were included in the analysis. GLP-1R agonist groups achieved a greater weight loss than control groups (weighted mean difference −2.9 kg, 95% confidence interval –3.6 to –2.2; 21 trials, 6411 participants). We found evidence of intertrial heterogeneity, but no evidence of bias or small study effects in regression analyses. The results were confirmed in sequential analyses. We recorded weight loss in the GLP-1R agonist groups for patients without diabetes (–3.2 kg, –4.3 to –2.1; three trials) as well as patients with diabetes (–2.8 kg, –3.4 to –2.3; 18 trials). In the overall analysis, GLP-1R agonists had beneficial effects on systolic and diastolic blood pressure, plasma concentrations of cholesterol, and glycaemic control, but did not have a significant effect on plasma concentrations of liver enzymes. GLP-1R agonists were associated with nausea, diarrhoea, and vomiting, but not with hypoglycaemia. Conclusions The present review provides evidence that treatment with GLP-1R agonists leads to weight loss in overweight or obese patients with or without type 2 diabetes mellitus.

Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials

Abstract Objective To assess the effects of non-absorbable disaccharides (lactulose and lactitol) in patients with hepatic encephalopathy. Data sources Cochrane Hepato-Biliary Group controlled trials register, Cochrane Library, Medline, and Embase until March 2003; reference lists of relevant articles; authors and pharmaceutical companies. Review methods Randomised trials that compared non-absorbable disaccharides with placebo, no intervention, or antibiotics for hepatic encephalopathy were included. The primary outcome measures were no improvement of hepatic encephalopathy and all cause mortality. Results 22 trials were included. Compared with placebo or no intervention, non-absorbable disaccharides seemed to reduce the risk of no improvement in patients with hepatic encephalopathy (relative risk 0.62, 95% confidence interval 0.46 to 0.84, six trials). However, high quality trials found no significant effect (0.92, 0.42 to 2.04, two trials). Compared with placebo or no intervention, non-absorbable disaccharides had no significant effect on mortality (0.41, 0.02 to 8.68, four trials). Non-absorbable disaccharides were inferior to antibiotics in reducing the risk of no improvement (1.24, 1.02 to 1.50, 10 trials) and lowering blood ammonia concentration (weighted mean difference 2.35 μmol/l, 0.06 μmol/l to 13.45 μmol/l, 10 trials). There was no significant difference in mortality (0.90, 0.48 to 1.67, five trials). Conclusions There is insufficient evidence to support or refute the use of non-absorbable disaccharides for hepatic encephalopathy. Antibiotics were superior to non-absorbable disaccharides in improving hepatic encephalopathy, but it is unclear whether this difference is clinically important. Non-absorbable disaccharides should not serve as comparator in randomised trials on hepatic encephalopathy.

Evidence based diagnostics

Diagnostic tests are often much less rigorously evaluated than new drugs. It is time to ensure that the harms and benefits of new tests are fully understood

Banding ligation versus beta-blockers as primary prophylaxis in esophageal varices: systematic review of randomized trials.

OBJECTIVE:To compare banding ligation versus beta-blockers as primary prophylaxis in patients with esophageal varices and no previous bleeding.METHODS:Randomized trials were identified through electronic databases, reference lists in relevant articles, and correspondence with experts. Three authors extracted data. Random effects meta-analysis and metaregression were performed. The reported allocation sequence generation and concealment were extracted as measures of bias control.RESULTS:The initial searches identified 1,174 references. Sixteen trials were included. In 15 trials, patients had high-risk varices. Three trials reported adequate bias control. All trials reported mortality for banding ligation (116/573 patients) and beta-blockers (115/594 patients). Mortality in the two treatment groups was not significantly different in the trials with adequate bias control (relative risk 1.22, 95% CI 0.84–1.78) or unclear bias control (RR 1.02, 95% CI 0.75–1.39). Trials with adequate bias control found no significant difference in bleeding rates (RR 0.86, 95% CI 0.55–1.35). Trials with unclear bias control found that banding ligation significantly reduced bleeding (RR 0.56, 95% CI 0.41–0.77). Both treatments were associated with adverse events. In metaregression analyses, the estimated effect of ligation was significantly more positive if trials were published as abstracts. Likewise, the shorter the follow-up, the more positive the estimated effect of ligation.CONCLUSIONS:Banding ligation and beta-blockers may be used as primary prophylaxis in high-risk esophageal varices. The estimated effect of banding ligation in some trials may be biased and was associated with the duration of follow-up. Further high-quality trials are still needed.

The window hypothesis: haemodynamic and non-haemodynamic effects of β-blockers improve survival of patients with cirrhosis during a window in the disease

Cirrhosis is one of the most frequent and severe chronic diseases worldwide. In the initial stages it has few or no symptoms, but advanced stages of cirrhosis are characterised by reduced liver function, complications due to portal hypertension and neuroendocrine abnormalities with increased activity of the sympathetic nervous system (SNS) and renin-aldosterone axis. The prognosis is severe, with an increasing frequency of complications including variceal bleeding, ascites and spontaneous infections with subsequent development of hepatic encephalopathy and hepatorenal syndrome. More than one-third of patients diagnosed with cirrhosis develop oesophageal varices within 3 years after the diagnosis is made. Varices develop and later bleed when the portal pressure is increased and the hepatic vein pressure gradient (HVPG) is more than 10–12 mm Hg. Life-threatening spontaneous bacterial infections are another common complication of advanced cirrhosis. The infections are mainly triggered by gut bacterial translocation, which is the migration of microorganisms from the intestinal lumen to the mesenteric lymph nodes or other extraintestinal sites.1 Small intestinal bacterial overgrowth of Gram-negative rods, structural and functional alterations of the intestinal mucosa and deficiencies in defence mechanisms contribute to bacterial translocation.2 Increased serum levels of lipopolysaccharide binding protein and circulating bacterial DNA are markers of bacterial translocation and both predict a poor outcome in cirrhosis and ascites.3 4 Selective gut decontamination prevents spontaneous bacterial infections and improves survival in advanced cirrhosis.5 Non-selective β-blockers (BB) are the only drugs shown to improve survival in patients with cirrhosis and medium to large oesophageal varices.6 BB inhibit the binding of catecholamines (norepinephrine and epinephrine) to the β1 and β2 adrenoreceptors. β1 blockade reduces the cardiac output and β2 blockade leads to splanchnic …

Secretion of Glucose-Dependent Insulinotropic Polypeptide in Patients With Type 2 Diabetes: Systematic review and meta-analysis of clinical studies

OBJECTIVE To investigate glucose-dependent insulinotropic polypeptide (GIP) secretion in patients with type 2 diabetes and nondiabetic control subjects during oral glucose or meal tests. RESEARCH DESIGN AND METHODS Eligible trials were identified by The Cochrane Library, MEDLINE, Embase, and Web of Science. Data were retrieved and random-effects models for the primary meta-analysis, random-effects meta-regression, and subgroup and regression analyses were applied. RESULTS Random-effects meta-analysis of GIP responses in 23 trials during 28 different stimulation tests showed that patients with type 2 diabetes (n = 363) exhibited no significant differences (P = not significant) in peak plasma GIP, total area under the curve (tAUC), time-corrected tAUC (tAUC × min−1), and time-corrected incremental area under the curve (iAUC × min−1) in comparison with nondiabetic control subjects (n = 325) but had lower GIP responses as evaluated from iAUC (weighted mean difference, −648 pmol/L × min; 95% CI, −1,276 to −21). Fixed-effects models meta-analyses confirmed most of the results of the primary meta-analysis but showed iAUC × min−1 to be reduced and showed tAUC and tAUC × min−1 to be higher in diabetic patients. Random-effects meta-regression of the primary meta-analysis showed that age (peak GIP, tAUC, iAUC, and iAUC × min−1), BMI (tAUC, iAUC, and iAUC × min−1), and HbA1c (iAUC and iAUC × min−1) predicted some of the GIP outcomes. Post hoc subgroup analysis showed a negative influence of age and of HbA1c on GIP responses and showed a positive influence of BMI on GIP responses. CONCLUSIONS Our results suggest that patients with type 2 diabetes are characterized by preserved GIP secretion in response to oral glucose and meal tests. They also suggest that high BMI is associated with increased GIP responses but increasing age and HbA1c are associated with reduced GIP secretion.

Oral Branched-Chain Amino Acids Have a Beneficial Effect on Manifestations of Hepatic Encephalopathy in a Systematic Review with Meta-Analyses of Randomized Controlled Trials

Supplements with branched-chain amino acid (BCAA) have cerebral, metabolic, and nutritional effects that may benefit patients with hepatic encephalopathy (HE). We therefore conducted a systematic review on the effects of oral BCAAs compared with control supplements or placebo for patients with cirrhosis and recurrent overt or minimal HE. The quantitative analyses included data from 8 trials (n = 382 patients). Individual patient data were retrieved from 4 trials to recalculate outcomes (n = 255 patients). The mean dose of the oral BCAA supplements was 0.25 g/(kg body weight · d). Random effects meta-analysis showed that improvements in HE manifestations were registered for 87 of 172 patients in the BCAA group compared with 56 of 210 controls [risk ratio = 1.71 (95% CI: 1.17, 2.51) number needed to treat = 5 patients]. The effect of BCAAs differed (P = 0.04) for patients with overt [risk ratio = 3.26 (95% CI: 1.47, 7.22)] and minimal HE [risk ratio = 1.32 (95% CI: 0.97, 1.79)]. Subgroup, sensitivity, regression, and sequential analyses found no other sources of heterogeneity or bias. BCAA supplements had no effect on mortality or markers of nutritional status and did not induce adverse events. In conclusion, oral BCAA supplements improve manifestations of HE but have no effect on survival.

Lactulose, rifaximin or branched chain amino acids for hepatic encephalopathy: what is the evidence?

Hepatic encephalopathy (HE) is a serious complication of acute and chronic liver disease associated with severe morbidity and mortality. We performed updated random effects meta-analyses to evaluate the evidence for non-absorbable disaccharides (lactulose and lactitol), rifaximin and branched chain amino acids (BCAA). A meta-analysis of randomized trials showed that, compared with placebo or no intervention, non-absorbable disaccharides have beneficial effects on HE manifestations and prevention of HE episodes. The addition of rifaximin to non-absorbable disaccharides versus rifaximin alone was more beneficial than non-absorbable disaccharides used alone on both outcome measures. Likewise, a meta-analysis of randomised controlled trials found that oral BCAA supplements have beneficial effects on manifestations of HE compared with control supplements. The effect was found in a variety of clinical settings. No convincing effects of intravenous BCAA for episodic HE were identified. In conclusion, evidence-based treatment recommendations for patients with HE should include non-absorbable disaccharides combined with rifaximin or BCAA. Additional evidence is needed to evaluate the effect of combining all three interventions.

Effect of the EndoBarrier Gastrointestinal Liner on obesity and type 2 diabetes: a systematic review and meta‐analysis

Compared with bariatric surgery, less invasive and reversible techniques to counteract obesity and type 2 diabetes (T2D) have been developed, including the EndoBarrier Gastrointestinal Liner [duodenal‐jejunal bypass sleeve (DJBS)]. We conducted a systematic review and meta‐analyses of eligible trials to evaluate the efficacy and safety of the DJBS. Five randomized controlled trials (RCTs; 235 subjects) and 10 observational studies (211 subjects) were included. The risk of bias was evaluated as high in all studies. The mean body mass index ranged from 30 to 49.2 kg/m2 and 10–100% of the subjects had T2D. Meta‐analysis showed that the DJBS was associated with significant mean differences in body weight and excess weight loss of −5.1 kg [95% confidence interval (CI) −7.3, −3.0; four trials; n = 151; I2 = 37%] and 12.6% (95% CI 9.0, 16.2; four trials; n = 166; I2 = 24%), respectively, compared with diet modification. The mean differences in glycated haemoglobin (−0.9%; 95% CI −1.8, 0.0) and fasting plasma glucose (−3.7 mM; 95% CI −8.2, 0.8) among subjects with T2D did not reach statistical significance. Adverse events consisted mainly of abdominal pain, nausea and vomiting. No deaths occurred. Future high‐quality long‐term RCTs are needed to further assess efficacy and safety.