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Meta-Analysis
. 2016 Nov 11;11(11):e0166125.
doi: 10.1371/journal.pone.0166125. eCollection 2016.

Benefits and Harms of Sodium-Glucose Co-Transporter 2 Inhibitors in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis

Heidi Storgaard  1 , Lise L Gluud  2 , Cathy Bennett  3 , Magnus F Grøndahl  1 , Mikkel B Christensen  1   4 , Filip K Knop  1   5   6 , Tina Vilsbøll  1   5
Affiliations
Meta-Analysis

Benefits and Harms of Sodium-Glucose Co-Transporter 2 Inhibitors in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis

Heidi Storgaard et al. PLoS One. .

Abstract

Objective: Sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are a novel drug class for the treatment of diabetes. We aimed at describing the maximal benefits and risks associated with SGLT2-i for patients with type 2 diabetes.

Design: Systematic review and meta-analysis.

Data sources and study selection: We included double-blinded, randomised controlled trials (RCTs) evaluating SGLT2-i administered in the highest approved therapeutic doses (canagliflozin 300 mg/day, dapagliflozin 10 mg/day, and empagliflozin 25 mg/day) for ≥12 weeks. Comparison groups could receive placebo or oral antidiabetic drugs (OAD) including metformin, sulphonylureas (SU), or dipeptidyl peptidase 4 inhibitors (DPP-4-i). Trials were identified through electronic databases and extensive manual searches. Primary outcomes were glycated haemoglobin A1c (HbA1c) levels, serious adverse events, death, severe hypoglycaemia, ketoacidosis and CVD. Secondary outcomes were fasting plasma glucose, body weight, blood pressure, heart rate, lipids, liver function tests, creatinine and adverse events including infections. The quality of the evidence was assessed using GRADE.

Results: Meta-analysis of 34 RCTs with 9,154 patients showed that SGLT2-i reduced HbA1c compared with placebo (mean difference -0.69%, 95% confidence interval -0.75 to -0.62%). We downgraded the evidence to 'low quality' due to variability and evidence of publication bias (P = 0.015). Canagliflozin was associated with the largest reduction in HbA1c (-0.85%, -0.99% to -0.71%). There were no differences between SGLT2-i and placebo for serious adverse events. SGLT2-i increased the risk of urinary and genital tract infections and increased serum creatinine, and exerted beneficial effects on bodyweight, blood pressure, lipids and alanine aminotransferase (moderate to low quality evidence). Analysis of 12 RCTs found a beneficial effect of SGLT2-i on HbA1c compared with OAD (-0.20%, -0.28 to -0.13%; moderate quality evidence).

Conclusion: This review includes a large number of patients with type 2 diabetes and found that SGLT2-i reduces HbA1c with a notable increased risk in non-serious adverse events. The analyses may overestimate the intervention benefit due bias.

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Conflict of interest statement

HS has received lecture fees from Advisory Boards of AstraZeneca, Boehringer Ingelheim Pharmaceuticals, and Bristol-Myers Squibb and has participated in Advisory Boards of AstraZeneca and Boehringer Ingelheim Pharmaceuticals. FKK has received lecture fees from, participated in Advisory Boards of and/or consulted for AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly and Company, Gilead Sciences, Merck Sharp & Dohme, Novartis, Novo Nordisk, Ono Pharmaceuticals, Sanofi and Zealand Pharma. TV has received lecture fees from, participated in Advisory Boards of and/or consulted for Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly and Company, Merck Sharp & Dohme, Novo Nordisk and Sanofi. CB is the proprietor of Systematic Research Ltd, a company providing research services, and is an employee of that company, and thus she received consultancy fees for participation in the project. LLG, MG, MC and CB declare no relationships with any organisations that might have an interest in the submitted work within the last three years, or no other relationships or activities that could have influenced the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Flowchart for identification and selection of included trials.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart.
Fig 2
Fig 2. Change in glycated haemoglobin: forest plot of randomized controlled trials comparing sodium-glucose co-transporter 2 inhibitors (SGLT2-i) versus placebo.
The plot shows subgroups of trials assessing the different SGLT2-i.
Fig 3
Fig 3. Change in glycated haemoglobin: forest plot of randomized controlled trials comparing sodium-glucose so-transporter 2 inhibitors (SGLT2-i) versus oral antidiabetic drugs (OAD).
The plot shows subgroups of trials assessing the different OAD.
See this image and copyright information in PMC

References

    1. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet. 2014;383(9922):1068–83. 10.1016/S0140-6736(13)62154-6 - DOI - PMC - PubMed
    1. Gaede P, Vedel P, Larsen N, Jensen GVH, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383–93. 10.1056/NEJMoa021778 - DOI - PubMed
    1. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405–12. - PMC - PubMed
    1. FDA. Briefing document NDA 204042 Invokana (canagliflozin) tablets. 2013.
    1. FDA. Briefing document NDA 202293: Dapagliflozin oral tablets, 5 and 10mg. 2013.

MeSH terms