Performing meta-analysis with incomplete statistical information in clinical trials

<p>Abstract</p> <p>Background</p> <p>Results from clinical trials are usually summarized in the form of sampling distributions. When full information (mean, SEM) about these distributions is given, performing meta-analysis is straightforward. However, when some of the sampling distributions only have mean values, a challenging issue is to decide how to use such distributions in meta-analysis. Currently, the most common approaches are either ignoring such trials or for each trial with a missing SEM, finding a similar trial and taking its SEM value as the missing SEM. Both approaches have drawbacks. As an alternative, this paper develops and tests two new methods, the first being the prognostic method and the second being the interval method, to estimate any missing SEMs from a set of sampling distributions with full information. A merging method is also proposed to handle clinical trials with partial information to simulate meta-analysis.</p> <p>Methods</p> <p>Both of our methods use the assumption that the samples for which the sampling distributions will be merged are randomly selected from the same population. In the prognostic method, we predict the missing SEMs from the given SEMs. In the interval method, we define intervals that we believe will contain the missing SEMs and then we use these intervals in the merging process.</p> <p>Results</p> <p>Two sets of clinical trials are used to verify our methods. One family of trials is on comparing different drugs for reduction of low density lipprotein cholesterol (LDL) for Type-2 diabetes, and the other is about the effectiveness of drugs for lowering intraocular pressure (IOP). Both methods are shown to be useful for approximating the conventional meta-analysis including trials with incomplete information. For example, the meta-analysis result of Latanoprost versus Timolol on IOP reduction for six months provided in <abbrgrp><abbr bid="B1">1</abbr></abbrgrp> was 5.05 ± 1.15 (Mean ± SEM) with full information. If the last trial in this study is assumed to be with partial information, the traditional analysis method for dealing with incomplete information that ignores this trial would give 6.49 ± 1.36 while our prognostic method gives 5.02 ± 1.15, and our interval method provides two intervals as Mean ∈ [4.25, 5.63] and SEM ∈ [1.01, 1.24].</p> <p>Conclusion</p> <p>Both the prognostic and the interval methods are useful alternatives for dealing with missing data in meta-analysis. We recommend clinicians to use the prognostic method to predict the missing SEMs in order to perform meta-analysis and the interval method for obtaining a more cautious result.</p

Is the ADA/EASD algorithm for the management of type 2 diabetes (January 2009) based on evidence or opinion? A critical analysis

The ADA and the EASD recently published a consensus statement for the medical management of hyperglycaemia in patients with type 2 diabetes. The authors advocate initial treatment with metformin monotherapy and lifestyle modification, followed by addition of basal insulin or a sulfonylurea if glycaemic goals are not met (tier 1 recommendations). All other glucose-lowering therapies are relegated to a secondary (tier 2) status and only recommended for selected clinical settings. In our view, this algorithm does not offer physicians and patients the appropriate selection of options to individualise and optimise care with a view to sustained control of blood glucose and reduction both of diabetes complications and cardiovascular risk. This paper critically assesses the basis of the ADA/EASD algorithm and the resulting tiers of treatment options

Long-term therapy with addition of pioglitazone to metformin compared with the addition of gliclazide to metformin in patients with type 2 diabetes: a randomized, comparative study.

BACKGROUND: This 52-week, randomized, double-blind study compared the efficacy and safety of metformin plus pioglitazone with the established combination of metformin plus gliclazide in type 2 diabetes mellitus. METHODS: Patients with poorly controlled type 2 diabetes (HbA1c &gt; or = 7.5% to &lt; or =11.0%) received either pioglitazone 15 mg o.d. (titrated up to 45 mg; n = 317) or gliclazide 80 mg o.d. (titrated up to 320 mg; n = 313) and metformin at the pre-study dose. HbA1c, fasting plasma glucose (FPG), insulin, lipids and the urinary albumin/creatinine ratio were measured. RESULTS: There were no significant differences in HbA1c (1% decrease in both groups) and FPG between groups. There was a decrease in fasting insulin in the pioglitazone group compared to an increase in the gliclazide group (p &lt; 0.001). There were significantly greater improvements in triglycerides and HDL-cholesterol in the metformin plus pioglitazone group compared to the metformin plus gliclazide group (p &lt; 0.001). Mean LDL-cholesterol decreased with metformin plus gliclazide and increased with metformin plus pioglitazone (p &lt; 0.001); however, this increase was considerably less marked than that in HDL-cholesterol. The mean urinary albumin/creatinine ratio was reduced by 10% in the metformin plus pioglitazone group compared to an increase of 6% in the metformin plus gliclazide group (p = 0.027). The incidence of adverse events was comparable between groups and both combinations were well tolerated. CONCLUSIONS: Compared to the established combination of metformin plus gliclazide, this study indicates potential benefits of addition of pioglitazone to metformin in terms of improvements in microalbuminuria and specific abnormalities associated with diabetic dyslipidemia

A long-term comparison of pioglitazone and gliclazide in patients with Type 2 diabetes mellitus: a randomized, double-blind, parallel-group comparison trial.

AIMS: This study compared the effects of pioglitazone and gliclazide on metabolic control in drug-naive patients with Type 2 diabetes mellitus. METHODS: A total of 1270 patients with Type 2 diabetes were randomized in a parallel-group, double-dummy, double-blind study. Patients with poorly controlled Type 2 diabetes (HbA1c 7.5-11%), despite dietary advice, received either pioglitazone up to 45 mg once daily or gliclazide up to 160 mg two times daily. Primary efficacy endpoint was change in HbA1c from baseline to the end of the study. Secondary efficacy endpoints included change in fasting plasma glucose, fasting plasma insulin and plasma lipids. At selected centres, oral glucose tolerance tests were performed and C-peptide and pro-insulin levels were measured. RESULTS: Mean HbA1c values decreased by the same amount in the two treatment groups from baseline to week 52 [pioglitazone: -1.4%; gliclazide: -1.4%; (90% CI: -0.18 to 0.02)]. A significantly greater mean reduction in fasting plasma glucose was observed in the pioglitazone group (2.4 mmol/l) than in the gliclazide group [2.0 mmol/l; treatment difference -0.4 mmol/l in favour of pioglitazone; P = 0.002; (95% CI: -0.7 to -0.1)]. Improvements in high-density lipoprotein cholesterol (HDL-C) and total cholesterol/HDL-C were greater with pioglitazone than with gliclazide (P &lt; 0.001). The frequencies of adverse events were comparable between the two treatment groups, but more hypoglycaemic events were reported for gliclazide, whereas twice as many patients reported oedema with pioglitazone than with gliclazide. CONCLUSIONS: Pioglitazone monotherapy was equivalent to gliclazide in reducing HbA1c, with specific differences between treatments in terms of mechanism of action, plasma lipids and adverse events

One-year glycemic control with a sulfonylurea plus pioglitazone versus a sulfonylurea plus metformin in patients with type 2 diabetes.

OBJECTIVE: The goal was to assess the 1-year efficacy and safety of the addition of pioglitazone or metformin to existing sulfonylurea (SU) therapy in patients with inadequately controlled type 2 diabetes. RESEARCH DESIGN AND METHODS: In this multicenter, double-blind study, patients were randomized to receive either pioglitazone 15 mg (n = 319) or metformin 850 mg (n = 320) and up to 45 mg/day and 2,550 mg/day, respectively. The primary efficacy endpoint was HbA(1c) at week 52. Fasting plasma glucose, insulin, and lipid profiles were also measured. RESULTS: HbA(1c) was reduced by 1.20% in the SU plus pioglitazone group and 1.36% in the SU plus metformin group, and fasting plasma glucose was reduced by 2.2 and 2.3 mmol/l in the respective groups. Fasting insulin levels were also reduced (pioglitazone arm -1.3 micro IU/ml; metformin arm -0.8 micro IU/ml). There were no significant between-treatment differences in these three parameters. Pioglitazone addition to SU significantly reduced triglycerides (-16 vs. -9%; P = 0.008) and increased HDL cholesterol (14 vs. 8%; P &lt; 0.001) compared with metformin addition. LDL cholesterol was increased 2% by the addition of pioglitazone and decreased 5% by the addition of metformin to SU (P &lt; 0.001). Urinary albumin-to-creatinine ratio was reduced by 15% in the SU plus pioglitazone group and increased 2% in the SU plus metformin group (P = 0.017). Both combinations were well tolerated with no evidence of hepatic or cardiac toxicity in either group. CONCLUSIONS: Clinically equivalent improvements in glycemic control were observed for both combinations. Compared with metformin plus SU, addition of pioglitazone to SU resulted in a reduction of the urinary albumin-to-creatinine ratio, a small but significant rise in LDL cholesterol, and significantly greater improvements in triglyceride levels and HDL cholesterol levels. Metformin plus SU was associated with a significant reduction in LDL cholesterol. SU plus pioglitazone is an effective and well-tolerated combination regimen that may provide additional beneficial effects for patients with type 2 diabetes

Avaliação de dois esquemas de monitorização domiciliar em pacientes com diabetes mellitus do tipo 1 Evaluación de dos esquemas de monitorización domiciliar en pacientes com diabetes mellitus tipo 1 Evaluation of two monitoring schemes in type 1 diabetes mellitus patients

O estudo teve por objetivo avaliar a efetividade de esquemas de monitorização domiciliar sangüíneo e urinário, na obtenção de adequado controle glicêmico, em pacientes com diabetes mellitus do tipo 1, em regime quinzenal de ajuste terapêutico; durante 6 meses de participação em grupos educativos. A amostra foi de 34 pacientes divididos em dois grupos. Os pacientes do grupo A realizaram monitorização domiciliar da glicemia capilar 1 vez ao dia e os do grupo B realizaram monitorização domiciliar da glicosúria 1 vez ao dia, conforme esquemas preconizados. Estes esquemas possibilitaram construção de perfis e de ajustes terapêuticos. Os resultados mostraram que o uso sistemático dos testes domiciliares sangúíneos e urinários da forma prescrita, não proporcionou melhora significante no controle metabólico em nenhum dos dois grupos. Entretanto, favoreceu o processo educativo e possibilitou reflexões sobre a necessidade de intensificação da monitorização glicêmica.<br>Este estudio tiene como objetivo evaluar la efectividad de dos esquemas de monitorización sanguíneo y de orina a nivel domiciliar, para obtener un adecuado control glicémico en pacientes con diabetes mellitus tipo 1. El ajuste terapéutico se realizó a cada quince dias en el plazo de seis meses com la participación en grupos educativos. La muestra stubo formada por 34 pacientes divididos en dos grupos: los pacientes del grupo A realizaron monitorización domiciliar de la glicemia capilar una vez al dia y los del grupo B hicieron monitorización de la glicosuria también una vez al dia según esquemas pre-establecidos. Estos esquemas posibilitaron la construción de los perfiles y ajustes terapéuticos. Los resultados indicaron que el uso de los tests domiciliares sanguíneos y orinarios pre-estabelecidos en los dos grupos, no proporcionaran una mejoría significativa en el control metabólico. Sin embargo, favoreció en el proceso educativo, posibilitando reflexiones sobre la necesidad de intensificar la monitorización glicémica en el domicilio.<br>The goal of this study was to evaluate the effectiveness of two monitoring schemes(blood and urine) in the metabolic control of type l diabetic patients, in biweekly therapeutic adjustments, along 6 months of participation in the educational groups. A sample of 34 patients was divided in two groups. The interventions proposed to group A were daily blood glucose monitoring, during three consecutive days for each period (before breakfast, before lunch, before dinner and before bed) and biweekly in the dawn. For the other group B was proposed daily urine glucose monitoring, during three consecutive days for each period (before breakfast, before lunch, before dinner and before bed). These schemes were used to construct glycemic profile and to determine the therapeutic adjustments. The results evidenced that there was no significant statistical difference in the metabolic control after proposed intervention in each group. In spite of this, the monitoring facilitated the educacional process and the considerations about the use of more intensive monitoring schemes