Extent of use of artificial intelligence & machine learning protocols in cancer diagnosis: A scoping review.

Background & objectives: Artificial intelligence (AI) and machine learning (ML) have shown promising results in cancer diagnosis in validation tests involving retrospective patient databases. This study was aimed to explore the extent of actual use of AI/ML protocols for diagnosing cancer in prospective settings. Methods: PubMed was searched for studies reporting usage of AI/ML protocols for cancer diagnosis in prospective (clinical trial/real world) setting with the AI/ML diagnosis aiding clinical decision-making, from inception till May 17, 2021. Data pertaining to the cancer, patients and the AI/ML protocol were extracted. Comparison of AI/ML protocol diagnosis with human diagnosis was recorded. Through a post hoc analysis, data from studies describing validation of various AI/ML protocols were extracted. Results: Only 18/960 initial hits (1.88%) utilized AI/ML protocols for diagnostic decision-making. Most protocols used artificial neural network and deep learning. AI/ML protocols were utilized for cancer screening, pre-operative diagnosis and staging and intra-operative diagnosis of surgical specimens. The reference standard for 17/18 studies was histology. AI/ML protocols were used to diagnose cancers of the colorectum, skin, uterine cervix, oral cavity, ovaries, prostate, lungs and brain. AI/ML protocols were found to improve human diagnosis, and had either similar or better performance than the human diagnosis, especially made by the less experienced clinician. Validation of AI/ML protocols was described by 223 studies of which only four studies were from India. Also there was a huge variation in the number of items used for validation. Interpretation & conclusions: The findings of this review suggest that a meaningful translation from the validation of AI/ML protocols to their actual usage in cancer diagnosis is lacking. Development of regulatory framework specific for AI/ML usage in healthcare is essential.

Real-World Evidence: A Primer.

Real-world evidence (RWE) is clinical evidence on a medical product's safety and efficacy that is generated using real-world data (RWD) resulting from routine healthcare delivery. There are several sources of RWD, including electronic health records (EHRs), registries, claims/billing data, and patient-generated data, as well as those from mobile health applications and wearable devices. Real-world data from these sources can be collected and analysed through different study designs such as prospective and retrospective cohort studies, case-control studies, and pragmatic clinical trials. Real-world evidence in the form of post-marketing surveillance has been extensively used to generate pharmacovigilance data. Of late, it has been realised that, apart from safety, RWE has additional applications in different stages of the drug approval cycle, and can be used to optimize the design of randomised controlled trials (RCTs). There has been an increasing awareness and acceptance of RWE from different stakeholders, including physicians, pharmaceutical companies, payers, regulators, and patients. Several regulatory authorities have also created frameworks and guidelines for efficient harnessing of RWE while acknowledging several challenges in RWD collection and analysis. The purpose of this review is to offer an outline of the current information on RWE, its advantages and disadvantages, as well as the associated challenges and ways to overcome them, while also throwing some light on the future of RWE.

Nature and mechanism of immune boosting by Ayurvedic medicine: A systematic review of randomized controlled trials.

BACKGROUND: Many Ayurvedic preparations are claimed to have immune-boosting properties, as suggested in various published randomized clinical trials (RCTs). AIM: To compile evidence on the nature and mechanism of immune system enhancement by Ayurvedic preparations in healthy and sick individuals. METHODS: After prospectively registering study protocol with PROSPERO, we searched PubMed, DOAJ, Google Scholar, three dedicated Ayurveda research portals, two specialty Ayurveda journals, and reference lists for relevant records published until February 6, 2021 using appropriate search strategies. Baseline features and data pertaining to the nature and mechanism of immune system function were extracted from all eligible records. Methodological quality was assessed using the Cochrane RoB-2 tool. RESULTS: Of 12554 articles screened, 19 studies reporting 20 RCTs (17 parallel group design, three crossover design) with 1661 unique patients were included; 11/19 studies had Indian first authors. Healthy population was included in nine studies, of which one study included pregnant women and two included pediatric population; remaining studies included patients with different health conditions, including one study with coronavirus disease 2019 patients. A total of 21 Ayurvedic interventions were studied, out of which five were composite mixtures. The predominant route of administration was oral; dose and frequency of administration of the intervention varied across the studies. The results reported with five RCTs exploring five Ayurvedic interventions were incomplete, ambiguous, or confusing. Of the remaining 16 interventions, indirect evidence of immune enhancement was reported with four interventions, while lack of the same was reported with two interventions. Enhancement of T helper cells and natural killer cells was reported with three and four interventions, respectively, while the pooled results did not clearly point toward enhancement of other components of the immune system, including cytotoxic T cells, B lymphocytes, immunoglobulins, cytokines, complement components, leucocyte counts, and other components. Nine of the 20 RCTs had a high risk of bias, and the remaining 11 RCTs had some concerns according to RoB-2. CONCLUSION: Various Ayurvedic preparations appear to enhance the immune system, particularly via enhancements in natural killer cells and T helper cells.

Safety and Efficacy of Ivermectin and Doxycycline Monotherapy and in Combination in the Treatment of COVID-19: A Scoping Review.

INTRODUCTION AND OBJECTIVE: Ivermectin (IVM) and doxycycline (DOXY) have demonstrated in-vitro activity against SARS-CoV-2, and have a reasonable safety profile. The objective of this systematic review was to explore the evidence in the literature on the safety and efficacy of their use as monotherapy and combination therapy in COVID-19 management. METHODS: After prospectively registering the study protocol with the Open Science Framework, we searched PubMed, Google Scholar, clinicaltrials.gov, various pre-print servers and reference lists for relevant records published until 16 February, 2021 using appropriate search strategies. Baseline features and data pertaining to efficacy and safety outcomes were extracted separately for IVM monotherapy, DOXY monotherapy, and IVM + DOXY combination therapy. Methodological quality was assessed based on the study design. RESULTS: Out of 200 articles screened, 19 studies (six retrospective cohort studies, seven randomised controlled trials, five non-randomised trials, one case series) with 8754 unique patients with multiple stages of COVID-19 were included; four were pre-prints and one was an unpublished clinicaltrials.gov document. The comparator was standard care and 'hydroxychloroquine + azithromycin' in seven and three studies respectively, and two studies were placebo controlled; six studies did not have a comparator. IVM monotherapy, DOXY monotherapy and IVM + DOXY were explored in eight, five and five studies, respectively; one study compared IVM monotherapy and IVM + DOXY with placebo. While all studies described efficacy, the safety profile was described in only six studies. Efficacy outcomes were mixed with some studies concluding in favour of the intervention and some studies displaying no significant benefit; barring one study that described 9/183 patients with erosive esophagitis and non-ulcer dyspepsia with IVM + DOXY (without causality assessment details), there were no new safety signals of concern with any of the three interventions considered. The quality of studies varied widely, with five studies having a 'good' methodological quality. CONCLUSIONS: Evidence is not sufficiently strong to either promote or refute the efficacy of IVM, DOXY, or their combination in COVID-19 management. SYSTEMATIC REVIEW PROTOCOL REGISTRATION DETAILS: Open Science Framework: https://osf.io/n7r2j .

Importance of Evidence-Based Health Insurance Reimbursement and Health Technology Assessment for Achieving Universal Health Coverage and Improved Access to Health in India.

OBJECTIVE: To review the importance of evidence-based methods in health insurance reimbursement for achieving universal health coverage in India. METHODS: A narrative literature review was performed. RESULTS: The out-of-pocket (OOP) healthcare expenditure in India is among the highest in the world. This situation is despite the implementation of numerous government health schemes and the availability of a large number of health insurance programs, both public and private. Compromised quality of care in many public healthcare facilities is a major factor driving the average Indian citizen to increasingly depend upon private healthcare facilities, further escalating OOP spending. The low awareness and poor uptake of insurance policies among Indians is one of the biggest challenges in the implementation of universal health coverage (UHC) in India. The catastrophic burden of high OOP expenses on individual households could be reduced by taking steps to enhance health insurance uptake, which can be in turn achieved by strengthening the healthcare reimbursement system in India. CONCLUSIONS: The application of the principles of evidence-based healthcare for reimbursement requires the systematic assessment of all health technologies, which is already being done in developed countries. The enactment of health schemes such as Ayushman Bharat-Pradhan Mantri Jan Arogya Yojana and setting up of Health Technology Assessment in India are steps toward reducing OOP expenditure and achieving UHC in India. We review the importance and challenges of evidence-based reimbursement and health technology assessment toward achieving UHC in India.

Efficacy and Safety of EGFR Inhibitors in the Treatment of EGFRPositive NSCLC Patients: A Meta-Analysis.

BACKGROUND: We compared the response rates, survival rates, and safety profile of epidermal growth factor receptor (EGFR) inhibitors with non-targeted chemotherapy and older EGFR inhibitors when used to treat advanced non-small cell lung cancer (NSCLC) patients with activating EGFR mutations. METHODS: We searched PubMed, Cochrane Central Register of Controlled Trials, and clinicaltrial.- gov for randomized controlled trials published until 11-Feb-2020. Treatment outcomes were compared between EGFR inhibitor and pooled comparator; a subgroup analysis compared outcomes between EGFR inhibitor and non-targeted chemotherapy, and between newer and older EGFR inhibitors. RESULTS: Twenty-one studies with 4,250 unique patients were included. Significantly higher objective response rate (ORR) (odds ratio (OR) 2.28; 95% CI 2.00-2.61), higher disease control rate (DCR) (OR 2.3; 95% CI 1.88-3.06), and longer progression-free survival (PFS) (Hazard ratio (HR) 0.56; 95% CI 0.52-0.60) were observed in the EGFR inhibitor group compared to the pooled comparator group. Subgroup analysis revealed that the ORR, DCR, and PFS were significantly higher with EGFR inhibitors than non-targeted chemotherapy, and only PFS (and not ORR and DCR) was significantly longer with newer EGFR inhibitors than the older EGFR inhibitors. Overall survival (OS) was not significantly different between EGFR inhibitors and pooled comparator (HR 0.91; 95% CI 0.83-1.00) as well as in either of the subgroup analyses. Adverse events ≥ grade 3 and treatment discontinuation were significantly higher with non-targeted chemotherapy compared to the EGFR inhibitors. CONCLUSION: The benefits of prolongation of ORR, DCR, and PFS might not imply significantly improved OS after therapy with EGFR inhibitors when compared with non-targeted chemotherapy or older EGFR inhibitors.

Real world safety of bevacizumab in cancer patients: A systematic literature review of case reports.

BACKGROUND: Real-world safety of bevacizumab in cancer patients is limited. OBJECTIVE: To review the adverse drug reactions (ADRs) due to bevacizumab in cancer patients, in published case reports. METHODS: PubMed was searched; case reports of patients with any type of cancer, administered with bevacizumab (monotherapy/combination) and reported ADRs were included. Causality of ADRs was presented as reported in individual papers. ADRs were classified using the information in the USFDA-approved prescribing information (PI) of bevacizumab as 'Serious', 'Common', and 'Post-marketing surveillance' ADRs; ADRs not mentioned in the bevacizumab PI were termed as 'Non-label ADRs'. RESULTS: A total of 130 published papers comprising 154 cases from 22 different countries were included. Most papers (102/130; 78.46%) had moderate methodological quality. Age range of patients was 9-77 years. Off-label use of bevacizumab was found in 34/154 cases (22.08%). Ninety-six unique ADRs were found among 154 ADRs; most reported ADRs affected circulatory, digestive, and respiratory systems (33, 32, and 26 cases respectively). Most commonly reported ADRs were posterior leukoencephalopathy, fistulae, and gastrointestinal perforation (17, 17, and 16 cases respectively). Twenty-eight unique non-label ADRs (29.17%) were found. CONCLUSION: Bevacizumab is associated with more ADRs in the real world among cancer patients than those reported during clinical trials.

A Critical Overview of Systematic Reviews of Chemotherapy for Advanced and Locally Advanced Pancreatic Cancer using both AMSTAR2 and ROBIS as Quality Assessment Tools.

BACKGROUND: We performed a critical overview of published systematic reviews (SRs) of chemotherapy for advanced and locally advanced pancreatic cancer, and evaluated their quality using AMSTAR2 and ROBIS tools. MATERIALS AND METHODS: PubMed and Cochrane Central Library were searched for SRs on 13th June 2020. SRs with meta-analysis which included only randomized controlled trials and that had assessed chemotherapy as one of the treatment arms were included. The outcome measures, which were looked into, were progression-free survival (PFS), overall survival (OS), and adverse events (AEs) of grade 3 or above. Two reviewers independently assessed all the SRs with both ROBIS and AMSTAR2. RESULTS: Out of the 1,879 identified records, 26 SRs were included for the overview. Most SRs had concluded that gemcitabine-based combination regimes, prolonged OS and PFS, but increased the incidence of grade 3-4 toxicities when compared to gemcitabine monotherapy, but survival benefits were not consistent when gemcitabine was combined with molecular targeted agents. As per ROBIS, 24/26 SRs had 'high' risk of bias, with only 1/26 SR having 'low' risk of bias. As per AMSTAR2, 25/26 SRs had 'critically low', and 1/26 SR had 'low' confidence in the results. The study which scored 'low risk of bias' in ROBIS scored 'low confidence in results' in AMSTAR2. The inter- rater reliability for scoring the overall confidence in the SRs with AMSTAR2 and the overall domain in ROBIS was substantial; ROBIS: kappa=0.785, SEM=0.207, p<0.001; AMSTAR2: kappa= 0.649, SEM=0.323, p<0.001. CONCLUSION: Gemcitabine-based combination regimens can prolong OS and PFS but also worsen AEs when compared to gemcitabine monotherapy. The included SRs have an overall low methodological quality and high risk of bias as per AMSTAR2 and ROBIS respectively.

Hydroxychloroquine and Remdesivir in COVID-19: A critical analysis of recent events.

The world is going through an unprecedented medical emergency with no effective remedy for the SARS-CoV2 virus causing Covid-19. Two drugs used for other indications in the past, hydroxychloroquine (HCQ) and remdesivir (RDV), are sought to be repurposed to treat Covid-19. Both these drugs have received emergency use authorisation by the US Food and Drug Administration. In this review, we critically analyse the identification of and subsequent events concerning these two drugs as potential treatment options for Covid-19, and conclude by raising some ethical issues that require serious thought from the global scientific community concerned with using these two drugs against Covid-19.

Key Words: Covid-19, hydroxychloroquine, remdesivir, USFDA, emergency use authorisation

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Role of digital therapeutics and the changing future of healthcare.

With healthcare becoming digital, patients today are more empowered than ever before. As a result, digital health solutions have become the need of the hour to keep up with an increasing number of empowered patients participating in their own treatment decisions. Digital health encompasses various platforms and systems that apply technological solutions to enhance healthcare delivery. Digital therapeutics (DTx) is one such category of digital health solutions that provides evidence-based software-driven therapeutic interventions for the prevention and management of a medical disorder or disease. This review aims to provide a comprehensive overview of DTx, its functions and applications in healthcare, and associated regulatory aspects, among others.

Assessing the Low Influenza Vaccination Coverage Rate Among Healthcare Personnel in India: A Review of Obstacles, Beliefs, and Strategies.

BACKGROUND: Most countries recommend that their healthcare personnel be vaccinated against influenza in order to protect themselves as well as their patients. However despite the strong scientific rationale, recommendations and advocacy from health organizations, influenza vaccination coverage among healthcare personnel remains low. This has been attributed to various obstacles and a range of strategies have been implemented to increase uptake with varying levels of success. OBJECTIVES: To highlight the vaccination coverage, beliefs, and obstacles among healthcare personnel in India and to discuss strategies that can be implemented to improve influenza vaccination coverage. CONCLUSIONS: Various barriers are responsible for the low influenza vaccination coverage among Indian healthcare personnel. Many interventions are being practiced, but they need to be multidimensional keeping in mind that healthcare personnel value their autonomy in making decisions about vaccinations.

Efficacy and Safety of Non-Steroidal Anti-Androgens in Patients with Metastatic Prostate Cancer: Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Prostate cancer (PCa) is the sixth primary cause of cancer death. However, conflicts are present about the efficacy and safety of Non-steroidal anti-androgens (NSAA) for its treatment. The aim of this study was to assess the efficacy and safety of NSAAs versus any comparator for the treatment of advanced or metastatic PCa (mPCa). METHODS: MEDLINE and the Cochrane Library were searched. References of included studies and clinicaltrials.gov were also searched for relevant studies. Only English language studies after 1990 were considered for review. Randomized controlled trials (RCTs) examining the efficacy and safety of NSAAs as compared with any other comparator including surgery or chemotherapy in mPCa patients were included. The outcomes include efficacy, safety and the tolerability of the treatment. The Cochrane Risk of Bias Assessment Tool was used for quality assessment. Two authors were independently involved in the selection, extraction and quality assessment of included studies and disagreements were resolved by discussion or by consulting a third reviewer. RESULTS: Fifty-eight out of 1307 non-duplicate RCTs with 29154 patients were considered for the review. NSAA showed significantly better progression-free survival [PFS] (Hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.46-0.78; P=0.0001), time to distant metastasis or death [TTD] (HR, 0.80; 95% CI 0.73-0.91; P<0.0001), objective response (Odds ratio [OR], 1.64; 95% CI 1.06-2.54; P=0.03) and clinical benefits (OR, 1.33; 95% CI 1.08-1.63; P=0.006) as compared to the control group. There was no significant difference observed between the groups in terms of overall survival (HR, 0.95; 95%CI, 0.87-1.03; P=0.18) and time to progression (HR, 0.93; 95% CI 0.77-1.11; P=0.43). Treatment-related adverse events were more with the NSAA group, but the discontinuation due to lack of efficacy reason was 43% significantly lesser than the control group in patients with mPCa. Rest of the outcomes were appeared to be non-significant. CONCLUSION: Treatment with NSAA was appeared to be better efficacious with respect to PFS, TTD, and response rate with considerable adverse events when compared to the control group in patients with metastatic PCa.

Economics of Medical Devices in India.

Most of the industrial sectors of India have undergone major changes in the post-liberalization period. During this period, India has become self-reliant in drugs; however, still, 75% of the medical devices are imported in India. According to WHO, almost all devices present in the developing countries have been designed for use in the industrialized countries. With the increase in incidence of non-communicable diseases and decrease in communicable diseases; increase in survival rates and decrease in mortality rates, and increase in ageing population, the healthcare demands have changed in the last decade. In addition to these parameters, aware patients and healthcare professionals, requirement of achieving national targets of healthcare and close proximity to the developed world, is giving a push to the development of indigenous medical device industry. However, the rules and regulations governing medical devices are ambiguous and vague. The Health Ministry of India has notified Medical Devices Rules, 2016, for regulating manufacturing/import/sale/clinical investigation and other related matters concerning medical devices. In addition, the government is funding the start-up industries in medical devices sector. Furthermore, government has taken the initiative of inverted duty structure in India. Also, special med tech zones are being set-up, which will enhance the production at local levels for the local population and will also generate employment for local people.

The Emerging Role of Patient-Reported Outcomes (PROs) in Clinical Trials: An Indian Perspective.

In an attempt to reduce costs of clinical trials and increase recruitments, pharmaceutical companies have been shifting their trials to offshore locations in Asia, Africa, the Middle East, Eastern Europe, and Latin America. Hence, methods for conducting clinical trials need to be adapted to the varying languages, cultures, ethnicities, and socioeconomic groups of these regions. This is of prime importance in the collection of patient-reported outcome (PRO) data. To ensure correct capturing of PRO data from multiregional sites, it is important that the tools for data collection are adapted to the respective cultures, and the data collected have the same interpretation across cultures (cross-cultural equivalence). This article deals with challenges involved in the adaptation of PRO measures to various cultures, especially of those used for multiregional trials being conducted in the developing world.

Real world evidence: An Indian perspective.

Randomized controlled trials (RCTs) are the gold standard for measuring the safety and efficacy of drugs. However, they are being challenged by payers and health care providers since they are looking for real world evidence (RWE) to validate whether the new intervention provides similar safety and efficacy as reported in RCT data. RWE uses real world data (RWD) to generate insight, foresight, and explorative findings on diseases, products, and patient populations. There are varied sources of RWD such as administrative data, large pragmatic trials, registries, electronic health records, and health surveys. RWE approaches are increasingly becoming the normal practice in developed countries to bring a product to the healthcare market and to ensure its significance in clinical practice. The Indian healthcare sector is growing at a brisk pace and is grasping up with the principles of health economics and outcome research, thereby exhibiting the value of real-world insights in healthcare decision. India has taken a step toward RWE by developing a framework to assist health care providers in harmonizing RWD for economic, clinical, and humanistic outcome.

Importance of Economic Evaluation in Health Care: An Indian Perspective.

Health economic studies provide information to decision makers for efficient use of available resources for maximizing health benefits. Economic evaluation is one part of health economics, and it is a tool for comparing costs and consequences of different interventions. Health technology assessment is a technique for economic evaluation that is well adapted by developed countries. The traditional classification of economic evaluation includes cost-minimization, cost-effectiveness analysis, cost-utility analysis, and cost-benefit analysis. There has been uncertainty in the conduct of such economic evaluations in India, due to some hesitancy with respect to the adoption of their guidelines. The biggest challenge in this evolutionary method is lack of understanding of methods in current use by all those involved in the provision and purchasing of health care. In some countries, different methods of economic evaluation have been adopted for decision making, most commonly to address the question of public subsidies for the purchase of medicines. There is limited evidence on the impact of health insurance on the health and economic well-being of beneficiaries in developing countries. India is currently pursuing several strategies to improve health services for its population, including investing in government-provided services as well as purchasing services from public and private providers through various schemes. Prospects for future growth and development in this field are required in India because rapid health care inflation, increasing rates of chronic conditions, aging population, and increasing technology diffusion will require greater economic efficiency into health care systems.

Can Health Technology Assessment (HTA) provide a solution to tackle the increasing health-care expenditure in India?

The private health-care system in India is effective but expensive. Due to the absence of a comprehensive and well-penetrated insurance scheme that caters to the majority of the Indian population, most of the private health care consultations are out-of-pocket (OOP), and this is pushing many people to poverty. In this article, we describe the concept of health technology assessment (HTA), and review its possible role in improving the health-care system in India. We additionally comment on its present status and possible role of its implementation in the Indian context.

Comparative effectiveness research and its utility in In-clinic practice.

One of the important components of patient-centered healthcare is comparative effectiveness research (CER), which aims at generating evidence from the real-life setting. The primary purpose of CER is to provide comparative information to the healthcare providers, patients, and policy makers about the standard of care available. This involves research on clinical questions unanswered by the explanatory trials during the regulatory approval process. Main methods of CER involve randomized controlled trials and observational methods. The limitations of these two methods have been overcome with the help of new statistical methods. After the evidence generation, it is equally important to communicate the results to all the interested organizations. CER is beginning to have its impact in the clinical practice as its results become part of the clinical practice guidelines. CER will have far-reaching scientific and financial impact. CER will make both the treating physician and the patient equally responsible for the treatment offered.

Diagnostic Accuracy of Xpert Test in Tuberculosis Detection: A Systematic Review and Meta-analysis.

BACKGROUND: World Health Organization (WHO) recommends the use of Xpert MTB/RIF assay for rapid diagnosis of tuberculosis (TB) and detection of rifampicin resistance. This systematic review was done to know about the diagnostic accuracy and cost-effectiveness of the Xpert MTB/RIF assay. METHODS: A systematic literature search was conducted in following databases: Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews, MEDLINE, PUBMED, Scopus, Science Direct and Google Scholar for relevant studies for studies published between 2010 and December 2014. Studies given in the systematic reviews were accessed separately and used for analysis. Selection of studies, data extraction and assessment of quality of included studies was performed independently by two reviewers. Studies evaluating the diagnostic accuracy of Xpert MTB/RIF assay among adult or predominantly adult patients (≥14 years), presumed to have pulmonary TB with or without HIV infection were included in the review. Also, studies that had assessed the diagnostic accuracy of Xpert MTB/RIF assay using sputum and other respiratory specimens were included. RESULTS: The included studies had a low risk of any form of bias, showing that findings are of high scientific validity and credibility. Quantitative analysis of 37 included studies shows that Xpert MTB/RIF is an accurate diagnostic test for TB and detection of rifampicin resistance. CONCLUSION: Xpert MTB/RIF assay is a robust, sensitive and specific test for accurate diagnosis of tuberculosis as compared to conventional tests like culture and microscopic examination.

Efficacy and safety of canagliflozin among patients with type 2 diabetes mellitus: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the efficacy and safety of canagliflozin in combination therapy among patients with type 2 diabetes mellitus with inadequate glycemic control. METHODS: Two review authors independently searched for the relevant randomized controlled clinical trials from the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, IndMed, LILACS, and clinical trials registry www.clinicaltrials.gov. Primary outcomes for this review included: change in hemoglobin A1c (HbA1c) levels, fasting plasma glucose (FPG) levels and risk of occurrence of genital mycotic infections at 26 weeks. We combined results using mean difference (MD) for continuous data, and risk ratio (RR) for dichotomous data. RESULTS: Of the 124 identified reports, five RCTs with 3565 participants were eligible for the meta-analysis. All included studies had compared canagliflozin 100 mg and 300 mg once daily with placebo or sitagliptin 100 mg once daily. We judged that most of the studies had low risk of bias or unclear risk of bias in five major domains. Canagliflozin 300 mg once daily led to a significant decrease in HbA1c levels (IV Fixed -0.77, 95% CI [-0.90, -0.64] P < 0.00001) and FPG levels (IV Fixed -2.08; 95% CI [-2.32, -1.84], P <0.00001), body weight, systolic blood pressure and triglyceride levels after 26 weeks as compared to placebo. There was a also a significant difference in the efficacy of canagliflozin 300 mg and sitagliptin 100 mg once daily in favour of canagliflozin. Both doses of canagliflozin led to genital mycotic infections among males and females, urinary tract infections, pollakiuria, polyuria and postural dizziness. CONCLUSIONS: Canagliflozin significantly decreases HbA1c and FPG levels and body weight as compared to placebo among patients with inadequate glycemic control with an earlier regime of glucose lowering agents. Long term safety studies are required to evaluate the incidence of adverse events.