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      ["post_title"]=>
      string(229) "NCT02065791 - A Randomized, Double-blind, Event-driven, Placebo-controlled, Multicenter Study of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Subjects With Type 2 Diabetes Mellitus and Diabetic Nephropathy"
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      string(194) "nct02065791-a-randomized-double-blind-event-driven-placebo-controlled-multicenter-study-of-the-effects-of-canagliflozin-on-renal-and-cardiovascular-outcomes-in-subjects-with-type-2-diabetes-mell"
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      string(243) "https://dev-yoda.pantheonsite.io/clinical-trial/nct02065791-a-randomized-double-blind-event-driven-placebo-controlled-multicenter-study-of-the-effects-of-canagliflozin-on-renal-and-cardiovascular-outcomes-in-subjects-with-type-2-diabetes-mell/"
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  ["property_scientific_abstract"]=>
  string(3681) "Background

Metabolic surgery is an effective treatment for type 2 diabetes (T2DM) independent of preoperative body mass index (BMI). Several randomized controlled trials have demonstrated superior glycemic control following metabolic surgery compared to conservative therapy over at least five years of follow-up. Two recent RCTs inpatients with diabetic nephropathy and hypertension have also demonstrated the effectiveness

of metabolic surgery in patients with these disease with a BMI between 30-35 kg/m2. However, there was also significant progress in the medical treatment of T2D in the last years due to the introduction of GLP-1 receptor agonists and SLGT2 blocker. Both drug types have been repeatedly demonstrated that they both reduce cardiovascular events and mortality compared to standard care. Due to the overlapping timely development of metabolic surgery and the new drug classes for

treatment of T2D, there are no studies directly comparing the effects of metabolic surgery vs. the new diabetes drugs.

The meta-analysis is registered at PROSPERO (CRD42021266001). 

Objective

To indirectly compare the effectiveness of metabolic surgery vs. new diabetes drugs. 

Study Design:

Individual patient data network meta-analysis

Participants:

1. Patients with T2DM

2. With or without established cardiovascular risk

3. With or without established micro- or macrovascular complications

Outcomes

The main outcomes of interest are:

1. Overall mortality

2. Cardiovascular mortality

3. Serious adverse events (Clavien-Dindo III, IV and V according to the modified Clavien-Dindo Classification)

a. We developed a modification of the Clavien-Dindo classification which allows to assess medical complications in a similar fashion

4. Quality of life changes

Additional outcomes of interest are:

a. Cardiovascular events (if feasible specified by its components, i.e. myocardial

infarction, stroke, revascularization (stent, coronary bypass), peripheral arterial

disease, unstable angina pectoris, heart failure)

b. Weight loss

c. Type 2 DM-related complications

d. Microvascular complications (retinopathy, nephropathy, neuropathy)

e. Type 2 DM remission

f. HbA1c changes

g. Blood lipids changes

h. BP changes ?

Additional endpoints (possibly as separate publications):

Renal outcomes; Liver-related outcomes (if data available); Comparison of different surgical procedures 

Statistical Analysis:

For all outcomes appropriate effect measures will be used. The indirect comparison, adjusted for effect modifiers, between metabolic surgery and new diabetes drugs will be estimated using a multilevel network meta-regression (ML-NMR) for population-adjusted treatment comparison (Phillippo et al., J R Stat Soc Ser A Stat Soc. 2020 Jun;183(3):1189-1210. doi:10.1111/rssa.12579. ?Multilevel network meta-regression for population-adjusted treatment comparisons?). This approach is an extension of the standard NMA framework and enables the combination of IPD and AgD, where aggregated data is imputed from the IPD by

numerical integration over the covariate distribution in the AgD studies. An advantage of this approach is that aggregation bias is avoided and population-adjusted treatment estimates are received. Furthermore, this approach allows the estimation of a treatment effect for a specific

target population. The integration over the covariate distribution will be investigated and sensitivity analysis will be conducted."
  ["project_brief_bg"]=>
  string(489) "The objective of this network meta-analysis (NMA) is to indirectly compare the effectiveness of metabolic surgery vs. the new diabetes drugs. More specifically, the main focus is set on cardiovascular outcomes and mortality and specific morbidity rates. 

This research project should ultimately serve as a tool to support the creation of therapy concepts for diabetes mellitus patients, based on different base criteria and specific targets, after a careful benefit-risk assessment."
  ["project_specific_aims"]=>
  string(328) "As of current knowledge, surgical methods are expected to achieve a greater weight loss, comorbidity improvement and stronger reduction of future cardiovascular events than drug therapy. On the other side, severe adverse events (SAE) are expected to be more likely to happen amongst the surgical patients than the medical group."
  ["project_study_design"]=>
  array(2) {
    ["value"]=>
    string(7) "meta_an"
    ["label"]=>
    string(52) "Meta-analysis (analysis of multiple trials together)"
  }
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  ["project_purposes"]=>
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  }
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  ["project_research_methods"]=>
  string(545) "Eligibility criteria

On study level:

1. RCTs

2. Follow-up of at least five years (longer follow-up data not necessary)

3. Shorter follow-up RCTs can be included if helpful (i.e. trials by Cohen et al. and

Schiavone et al.).

4. Comparing either metabolic surgery or new diabetes drugs to standard care

On participant level:

1. Patients with type 2 diabetes

2. With or without established cardiovascular risk

3. With or without established micro- or macrovascular complications"
  ["project_main_outcome_measure"]=>
  string(1294) "The main outcomes of interest are:

1.	Overall mortality

2.	Cardiovascular  events (myocardial infarction, stroke, limb ischemia, cardiovascular mortality)

3.	Serious adverse events (Clavien-Dindo III, IV and V according to the modified Clavien-Dindo Classification)

a.	We developed a modification of the Clavien-Dindo classification which allows to assess medical complications in a similar fashion

4.	Quality of life changes

Additional outcomes of interest are:

a.	Cardiovascular events (if feasible specified by its components, i.e. myocardial infarction, stroke, revascularization (stent, coronary bypass), peripheral arterial disease, unstable angina pectoris, heart failure)

b.	Weight loss

c.	Type 2 Diabetes Mellitus-related complications

d.	Microvascular complications (retinopathy, nephropathy, neuropathy)

e.	Type 2 Diabetes Mellitus remission

f.	HbA1c changes

g.	Blood lipids changes (high density lipoprotein (HDL), low density lipoprotein (LDL), Triglycerides)

h.	Blood pressure changes 

Additional endpoints (possibly as separate publications):

1.	Renal outcomes

2.	Liver-related outcomes (if data available)

3.	Comparison of different surgical procedures"
  ["project_main_predictor_indep"]=>
  string(66) "Metabolic Surgery VS. modern diabetes mellitus type 2 drug therapy"
  ["project_other_variables_interest"]=>
  string(3) "N/A"
  ["project_stat_analysis_plan"]=>
  string(3586) "An important assumption of network analysis is transitivity that is in our case that the common comparator (standard care) is similar when it appears in the surgical and medical trials. The treatment of the medical-conservative cohorts in the surgical RCTs is according to the standards of medical care during that time. Similarly, the ?placebo? cohorts of the medical RCTs investigating new diabetes drugs are also according to the standards of medical care during that time. Therefore, the control groups of the surgical trials and the placebo groups of the medical trials are comparable regarding treatment. Hence, the transitivity assumption holds with respect to the treatments of the common comparator group and a three-armed RCT comparing all of the included interventions simultaneously is thus, in theory, possible.

There are effect modifiers whose distribution will presumably differ in the two direct comparisons. Patients in the medical trials have usually some sort of cardiovascular risk as inclusion criteria while this is not the case in the surgical trials. Patients in the new drug trials are older and tend to have more comorbidities.

Another aspect is that there will be individual participant data (IPD) as well as aggregated date (AgD) for both direct comparisons. There has been already experience in this sort of network meta-analysis with a Cochrane review which is about to be handed in.

Statistical approach:

For all outcomes appropriate effect measures will be used. The indirect comparison, adjusted for effect modifiers, between metabolic surgery and new diabetes drugs will be estimated using a multilevel network meta-regression (ML-NMR) for population-adjusted treatment comparison (Phillippo et al., J R Stat Soc Ser A Stat Soc. 2020 Jun;183(3):1189-1210. doi: 10.1111/rssa.12579. ?Multilevel network meta-regression for population-adjusted treatment comparisons?). This approach is an extension of the standard NMA framework and enables the combination of IPD and AgD, where aggregated data is imputed from the IPD by numerical integration over the covariate distribution in the AgD studies. An advantage of this approach is that aggregation bias is avoided and population-adjusted treatment estimates are received. Furthermore, this approach allows the estimation of a treatment effect for a specific target population. The integration over the covariate distribution will be investigated and sensitivity analysis will be conducted. In the network meta-analysis model random effects will be used with respect to between-study heterogeneity and to account for the independence of the studies.

The statistical analysis will be pre-specified and described in more details within a statistical analysis plan prior to the start of the meta-analysis. 

Handling missing data:

Patients with missing data in IPD studies will be excluded from the analysis.

For studies with AgD missing means and standard deviations will be imputed from reported statistics, such as median and measures of dispersion, using appropriate formulas considering the sample size as described in Wan, X., Wang, W., Liu, J. et al. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 14, 135 (2014). https://doi.org/10.1186/1471-2288-14-135

and Luo D, Wan X, Liu J, Tong T (2018): Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Statistical Methods in Medical Research, 27, 1785?805."
  ["project_timeline"]=>
  string(96) "Target Analysis Start Date: 08/2022 - 09/2022

Estimated Analysis Completion Date: 11/2022"
  ["project_dissemination_plan"]=>
  string(286) "Publication of main outcomes (mortality, cardiovascular events im premier journals (JAMA, The Lancet or comparable)

Subgroup analysis of more detailed outcomes in leading journals for the respective fields (JAMA Surgery or Annals of Surgery for comparison of surginal techniques)"
  ["project_bibliography"]=>
  string(4336) "
Three-Year Outcomes of Bariatric Surgery in Patients with Obesity and Hypertention, a Randomized Clinical Trial (Schiavon C. A. et al) DOI: 10.7326/M19-3781

Metabolic Surgery versus conventional medical therapy in patients with type 2 diabetes: 10-year follow up of an open-label, single-centre, randomised controlled trial (Mingrone G. et al.) DOI: 10.1016/S0140-6736(20)32649-0

Lifestyle Intervention and Medical Management with vs. Without Roux-en-Y Gstric Bypass and Control of Hemoglobin A1c, LDL Cholesterol, and Systolic Blood Pressure at 5 Years in the Diabetes Surgery Study (Ikramuddin S. et al.) DOI: 10.1001/jama.2017.20813.

Bariatric surgery vs Lifestyle Intervention for diabetes Treatment: 5-Year Outcomes From a Randomized Trial (Courcoulas A. et al.) DOI: 10.1210/clinem/dgaa006.

Bariatric Surgery versus Intensive Medical Therapy for Diabetes – 5-year Outcomes (Schauer P. et al.) ?DOI:?10.1056/NEJMoa1600869

Clinical and Patient-centered outcomes in obese Patients With Type 2 Diabetes 3 years after randomization to Roux-en-Y Gastric Bypass Durgery versus Intensive Lifestyle Management: The SLIMM-T2D Study (Simonson D. et al.) DOI: 10.2337/dc17-0487

Sustained 52-week efficacy and safety of triple therapy with dapagliflozin plus saxagliptin versus dual therapy with sitagliptin added to metformin in patients with uncontrolled type 2 diabetes (Handelsman Y. et al.) DOI:?10.1111/dom.13594

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial (Hernandez A. et al.) DOI: https://doi.org/10.1016/S0140-6736(18)32261-X

A 52-week randomized controlled trial of ipragliflozin or sitagliptin in type 2 diabetes combined with metformin: The N-ISM study (Kitazawa M. et al.) DOI: 10.1111/dom.14288

Efficacy and Safety of Dulaglutide 3.0 mg and 4.5 mg Versus Dulaglutide 1.5 mg in Metformin- Treated Patients With Type 2 Diabetes in a Randomized Controlled Trial (AWARD-11) (Frias J. P. et al.) doi: 10.2337/dc20-1473

Emfagliflozin, Cardiovascular Outcomes and Mortality in Type 2 Diabetes ? EMPA-REG Outcome (Zinman B. et al) DOI: 10.1056/NEJMoa1504720

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes ? LEADER Trial (Marso S. et al.) DOI: 10.1056/NEJMoa1603827

Efficacy and Safety of Once- Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 Diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial (Ahmann A. et al.) DOI: https://doi.org/10.2337/dc17-0417

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes (Marso S. et al) DOI: 10.1056/NEJMoa1607141.

Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes (Wiviott S. D. et al.) DOI: 10.1056/NEJMoa1812389

Efficacy, Safety and Tolerability of Oral Semaglutide vs Placebo added to insulin with or without metformin in Patients with Type 2 Diabetes: The PIONEER 8 Trial (Zinman D. et al.) DOI:10.2337/dc19-0898

Cardiovascular and Renal Outcomes with Empagliflozin in heart failure (Packer M. et al.) DOI: 10.1056/NEJMoa2022190

Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes (Holman R. et al.) doi: 10.1056/NEJMoa1612917

Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes (Neal B. et al.) DOI: 10.1056/NEJMoa1611925

Results of VERTIS SU extension study: safety and efficacy of ertugliflozin treatment over 104 weeks compared to glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin (Hollander P. et al.) DOI:https://doi.org/10.1080/03007995.2019.1583450

Phillippo et al., J R Stat Soc Ser A Stat Soc. 2020 Jun;183(3):1189-1210. doi: 10.1111/rssa.12579. ?Multilevel network meta-regression for population-adjusted treatment comparisons?

Wan, X., Wang, W., Liu, J. et al. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 14, 135 (2014). https://doi.org/10.1186/1471-2288-14-135

Luo D, Wan X, Liu J, Tong T (2018): Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Statistical Methods in Medical Research, 27, 1785?805.
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