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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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  ["project_title"]=>
  string(153) "Safety and Effectiveness of Sodium-Glucose Cotransporter-2 Inhibitors in Comparison with Glucagon-Like Peptide-1 Agonists on Weight Loss: A Meta-Analysis"
  ["project_narrative_summary"]=>
  string(514) " In the battle against the global obesity epidemic, medications initially designed for diabetes management, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, appear as potential agents for weight loss. The purpose of this meta-analysis is to review the existing literature to compare SGLT-2 inhibitors with GLP-1 receptor agonists effectiveness in terms of weight loss, and safety profile of cardiac, gastrointestinal, and renal adverse drug reactions (ADR)."
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    ["first_name"]=>
    string(7) "Jessica"
    ["last_name"]=>
    string(14) "Montanez Roque"
    ["degree"]=>
    string(16) "PharmD candidate"
    ["primary_affiliation"]=>
    string(42) "Lake Erie College of Osteopathic Medicine "
    ["email"]=>
    string(28) "JMontanezR97349@rx.lecom.edu"
    ["state_or_province"]=>
    string(2) "FL"
    ["country"]=>
    string(13) "United States"
  }
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    ["label"]=>
    string(68) "No external grants or funds are being used to support this research."
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  ["property_scientific_abstract"]=>
  string(2254) "Background 

Obesity has emerged as a pervasive and multifaceted public health challenge in the United States. In the battle against the global obesity epidemic, medications initially designed for diabetes management, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, appear as potential agents for weight loss. These medications are used off-label and an assessment of safety and efficacy are necessary.  



Objective

After conducting a preliminary meta-analysis, it was found that GI ADRs where more prevalent when using SGLT-2. We seek to conduct a more detailed examination of the individual patient level data of NCT02065791 to determine the presence of pre-existing GI conditions or other comorbidities among patients, heterogeneity, or the use of other medications that may be affecting the ADRs reported. 



Study design: A meta-analysis including  8 clinical trials where SGLT-2 inhibitors or GLP-1 receptor agonists were used to determine weight loss efficacy and, safety. New patient-level data will be utilized to identify additional factors that may be affecting safety and increasing severe GI ADRs.  



Study design

Meta-analysis



Participants: 

Total of 5,589 participants in the GLP-1 receptor agonist clinical trials and 5,969 participants in the SGLT-2 inhibitor clinical trials.



Primary Outcome Measure: Overall patient's weight loss in Kg per drug class 

Second Outcome Measure: Safety based on ADRs per drug class



Proposed  statistical analysis

NCT02065791 patient-level data will be utilized to identify serious adverse events influencing preliminary results of GI ADRs in the use of SGLT-2 inhibitors. Cardiac, renal and gastrointestinal severe ADRs will be evaluated along with this additional data. A statistical analysis will be performed using Review Manager 5.4,  R Studio, R version 4.3.1 and Microsoft® Excel® for Microsoft 365 MSO (Version 2308 Build 16.0.16731.20182) 32-bit.  

Z-tests and p-values will be calculated to determine if the data is statistically significant for safety in term of relative risk ratios. 



"
  ["project_brief_bg"]=>
  string(655) "In the battle against the global obesity epidemic, medications initially designed for diabetes management, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, appear as potential agents for weight loss. The purpose of this meta-analysis is to review the existing literature to compare SGLT-2 inhibitors with GLP-1 receptor agonists effectiveness in terms of weight loss, and safety profile of cardiac, gastrointestinal, and renal adverse drug reactions (ADR). The primary objective of this study is to investigate the weight loss efficacy and the secondary endpoint is to assess their safety profile. "
  ["project_specific_aims"]=>
  string(316) "This meta-analysis aims to conduct a more detailed examination of the individual patient level data to determine the presence of pre-existing renal conditions or other comorbidities among patients, heterogeneity, or the use of other medications that may be affecting the ADRs reported in NCT02065791.



"
  ["project_study_design"]=>
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    ["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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    [0]=>
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      ["value"]=>
      string(18) "summary_level_data"
      ["label"]=>
      string(32) "Summary-level data meta-analysis"
    }
    [1]=>
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      ["value"]=>
      string(52) "summary_level_data_meta_analysis_from_yoda_and_other"
      ["label"]=>
      string(69) "Meta-analysis using data from the YODA Project and other data sources"
    }
    [2]=>
    array(2) {
      ["value"]=>
      string(28) "research_on_comparison_group"
      ["label"]=>
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    }
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    ["label"]=>
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  ["project_research_methods"]=>
  string(2296) "Data source: Literature and clinical trials search conducted through PubMed, EMBASE, and Cochrane Library, and Clinical Trials.gov

Inclusion criteria:

For weight loss analysis:

Completed clinical trials of SLGT-2 and GLP-1 inhibitors containing a treatment group and a placebo group, where the outcome (weight loss), was expressed in the mean (SD) departure from the baseline in kg.

Search terms: “SGLT-2” and “obesity”, and “GLP-1” and “obesity”.

For ADR determination:

Completed clinical trials of SGLT-2 and GLP-1 inhibitors containing a treatment group and a placebo group, where the ADRs are expressed in a number of incidents in the following categories: GI, Renal, Cardiac; in the treatment or control groups.

Search terms: “SGLT-2” and “safety”, and “GLP-1” and “safety”.

Exclusion criteria:

Any research that referenced the same underlying clinical trial (duplicate data).

Any research that did not have mean (SD) weight loss for baseline represented in kg (not apples to apples data comparison for weight loss).

Studies where the data was represented in QALYs instead of weight loss.

Any study without a control group.

Studies which compared drug-to-drug without a control group.

Studies where the data could not be verified by the author.

Any research that did not meet the inclusion criteria above.



Analytical Plan Expansion:



1. Comprehensive Data Analysis: We plan to compare the requested patient-level data with data from other trials, enhancing the robustness and validity of our analysis.



2. Outcome Definitions: Our study will specify renal-related outcomes, employing clear and consistent definitions to accurately assess the ADRs.



3. Addressing Heterogeneity: Through advanced statistical techniques, including meta-regression and subgroup analysis, we will investigate how varying patient characteristics influence renal ADR occurrences.



Our revised approach and analysis plan are crafted to provide meaningful insights into the safety profile of SGLT-2 medications, potentially improving patient care by identifying risks associated with pre-existing conditions."
  ["project_main_outcome_measure"]=>
  string(143) "Primary Outcome Measure: Overall patient's weight loss in Kg per drug class 

Second Outcome Measure: Safety based on ADRs per drug class"
  ["project_main_predictor_indep"]=>
  string(142) "Mean Weight loss in Kg and number of ADRs in the following  body systems: cardiac, gastrointestinal, and renal adverse drug reactions.

"
  ["project_other_variables_interest"]=>
  string(3) "N/A"
  ["project_stat_analysis_plan"]=>
  string(591) "NCT02065791 patient-level data will be utilized to identify serious adverse events influencing preliminary results of GI ADRs in the use of SGLT-2 inhibitors. Cardiac, renal and gastrointestinal severe ADRs will be evaluated along with this additional data. A statistical analysis will be performed using Review Manager 5.4,  R Studio, R version 4.3.1 and Microsoft® Excel® for Microsoft 365 MSO (Version 2308 Build 16.0.16731.20182) 32-bit.  

Z-tests and p-values will be calculated to determine if the data is statistically significant for safety in term of relative risk ratios. "
  ["project_timeline"]=>
  string(215) "Project start date: April 10th, 2024

Analysis completion date: May 10th, 2024

Date for manuscript drafting: June 15th, 2024

Date for reporting results back to the YODA project: August 20th, 2024"
  ["project_dissemination_plan"]=>
  string(95) "A manuscript will be submitted to The Journal of the American Pharmacists Association (JAPhA). "
  ["project_bibliography"]=>
  string(8867) "
1Aronow, W. S., & Shamliyan, T. A. (2017). Comparative effectiveness and safety of empagliflozin on cardiovascular mortality and morbidity in adults with type 2 diabetes. Annals of Translational Medicine, 5(23), 455–455. https://doi.org/10.21037/atm.2017.08.43
2AstraZeneca. (2015, October 20). A Phase III Study of BMS-512148 (Dapagliflozin) in Patients With Type 2 Diabetes Who Are Not Well Controlled With Diet and Exercise. Clinicaltrials.gov. https://clinicaltrials.gov/study/NCT00528372?aggFilters=status:com&term=NCT00528372&r ank =1&tab=results#adverse-events 
3Babar M, Hussain M, Ahmad M, Akhtar L. Comparison Of Efficacy And Safety Profile Of  Empagliflozin As A Combination Therapy In Obese Type 2 Diabetic Patients. Journal  of Ayub Medical College, Abbottabad : JAMC 2021;33(2):188-91. [PubMed:  34137526] 
4Bays HE, Weinstein R, Law G, Canovatchel W. Canagliflozin: effects in overweight and  obese subjects without diabetes mellitus. Obesity (Silver Spring, Md.)  2014;22(4):1042-9. [PubMed: 24227660] 
5Boehringer Ingelheim. (2016, February 22). 12 Week Efficacy and Safety Study of Empagliflozin (BI 10773) in Hypertensive Patients With Type 2 Diabetes Mellitus. Clinicaltrials.gov. https://clinicaltrials.gov/study/NCT01370005?intr=Empagliflozin%2010%20MG%20placebo%20&agg%20Filters=status:com&page=2&rank=14&tab=results
6Davies M, Færch L, Jeppesen OK, Pakseresht A, Pedersen SD, Perreault L, et al.  Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2  diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled,  phase 3 trial. Lancet (London, England) 2021;397(10278):971-84. [PubMed:  33667417] 
7Eli Lilly and Company. (2021, October 20). A Study of Tirzepatide (LY3298176) in Participants With Type 2 Diabetes Not Controlled With Diet and Exercise Alone (SURPASS-1). Clinicaltrials.gov. https://clinicaltrials.gov/study/NCT03954834?tab=results#baseline-characteristics
8Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF. Dapagliflozin monotherapy in type 2  diabetic patients with inadequate glycemic control by diet and exercise: a  randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes care  2010;33(10):2217-24. [PubMed: 20566676] 
9Janssen Research & Development, LLC. (2019, December 05). Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE). Clinicaltrials.gov. https://clinicaltrials.gov/study/NCT02065791
10Johnson & Johnson Pharmaceutical Research & Development, L.L.C.. (2013, May 24). A Study of the Safety and Effectiveness of Canagliflozin (JNJ-28431754) in Promoting Weight Loss in Overweight and Obese Patients Who do Not Have Diabetes. Clinicaltrials.gov. https://clinicaltrials.gov/study/NCT00650806?tab=results#baseline-characteristics 
11Nassif ME, Windsor SL, Gosch K, Borlaug BA, Husain M, Inzucchi SE, et al.  Dapagliflozin Improves Heart Failure Symptoms and Physical Limitations Across the  Full Range of Ejection Fraction: Pooled Patient-Level Analysis From DEFINE-HF and  PRESERVED-HF Trials. Circulation. Heart failure 2023;16(7):e009837. [PubMed:  37203441] 
12Novo Nordisk A/S. (2018, January 19).Effect of Liraglutide on Body Weight in Non-diabetic Obese Subjects or Overweight Subjects With Co-morbidities: SCALE™ – Obesity and Pre-diabetes.Clinicaltrials.gov. https://clinicaltrials.gov/study/NCT01272219?tab=results#baseline-characteristics
13Novo Nordisk A/S. (2021, November 09). Research Study Investigating How Well Semaglutide Works in People With Type 2 Diabetes Suffering From Overweight or Obesity (STEP 2). Clinicaltrials.gov. https://clinicaltrials.gov/study/NCT03552757?tab=results#baseline-characteristics 
14Novo Nordisk A/S. (2022, January 19). Research Study Investigating How Well Semaglutide Works in People Suffering From Overweight or Obesity (STEP 4). Clinicaltrials.gov. https://clinicaltrials.gov/study/NCT03548987
15Perkovic Vlado, Jardine Meg J, Neal Bruce, Bompoint Severine, Heerspink Hiddo J L,  Charytan David M, et al. Canagliflozin and renal outcomes in type 2 diabetes and  nephropathy. N. Engl. J. Med. 2019;380(24):2295-306. 
16Perkovic Vlado, Jardine Meg J, Neal Bruce, Bompoint Severine, Heerspink Hiddo J L,  Charytan David M, et al. Supplementary Appendix to Canagliflozin and renal outcomes in type 2 diabetes and  nephropathy. N. Engl. J. Med. 2019;380(24):2295-306. (PDF updated June 13, 2019)
17Pi-Sunyer Xavier, Astrup Arne, Fujioka Ken, Greenway Frank, Halpern Alfredo, Krempf  Michel, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight. N. Engl.  J. Med. 2015;373(1):11-22.
18Rosenstock J, Wysham C, FrÃ-as JP, Kaneko S, Lee CJ, Fernández Landó L, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in 
patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3  trial. Lancet (London, England) 2021;398(10295):143-55. [PubMed: 34186022] 
19Rubino Domenica, Abrahamsson Niclas, Davies Melanie, Hesse Dan, Greenway Frank  L, Jensen Camilla, et al. Effect of continued weekly subcutaneous semaglutide vs  placebo on weight. JAMA 2021;325(14):1414-25. 
20Saint Luke’s Health System. (2022, April 21). Dapagliflozin Effect on Symptoms and Biomarkers in Patients With Heart Failure (DEFINE-HF). Clinicaltrials.gov. https://clinicaltrials.gov/study/NCT02653482 
21Tuttle KR, Levin A, Nangaku M, Kadowaki T, Agarwal R, Hauske SJ, Elsäßer A, Ritter I,  Steubl D, Wanner C, Wheeler DC. Safety of Empagliflozin in Patients With Type 2  Diabetes and Chronic Kidney Disease: Pooled Analysis of Placebo-Controlled  Clinical Trials. Diabetes Care. 2022 Jun 2;45(6):1445-1452. doi: 10.2337/dc21-2034.  PMID: 35472672; PMCID: PMC9210861.
 
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