Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis
Objective To estimate the association between the use of sodium glucose co-transporter-2 (SGLT2) inhibitors and postmarket harms as identified by drug regulatory agencies.Design We conducted a systematic review and meta-analysis of randomised controlled trials (RCT). Six large databases were searche...
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BMJ Publishing Group
2019-02-01
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| Series: | BMJ Open |
| Online Access: | https://bmjopen.bmj.com/content/9/1/e022577.full |
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| author | Kris Aubrey-Bassler John-Michael Gamble Jennifer R Donnan Catherine A Grandy Eugene Chibrikov Carlo A Marra Karissa Johnston Michelle Swab Jenna Hache Daniel Curnew Hai Nguyen |
| author_facet | Kris Aubrey-Bassler John-Michael Gamble Jennifer R Donnan Catherine A Grandy Eugene Chibrikov Carlo A Marra Karissa Johnston Michelle Swab Jenna Hache Daniel Curnew Hai Nguyen |
| author_sort | Kris Aubrey-Bassler |
| collection | DOAJ |
| description | Objective To estimate the association between the use of sodium glucose co-transporter-2 (SGLT2) inhibitors and postmarket harms as identified by drug regulatory agencies.Design We conducted a systematic review and meta-analysis of randomised controlled trials (RCT). Six large databases were searched from inception to May 2018. Random effects models were used to estimate pooled relative risks (RRs).Intervention SGLT2 inhibitors, compared with placebo or active comparators.Primary outcomes Acute kidney injury (AKI), diabetic ketoacidosis (DKA), urinary tract infections (UTI), bone fractures and lower limb amputations.Results We screened 2418 citations of which 109 were included. Most studies included one of four SGLT2 inhibitors, dapagliflozin, canagliflozin, empagliflozin and ipragliflozin. When compared with placebo, SGLT2 inhibitors were found to be significantly protective against AKI (RR=0.59; 95% CI 0.39 to 0.89; I2=0.0%), while no difference was found for DKA (RR 0.66; 95% CI 0.30 to 1.45, I2=0.0%), UTI (RR 1.02; 95% CI 0.95 to 1.09, I2=0.0%) or bone fracture (RR 0.87; 95% CI 0.69 to 1.09, I2=1.3%). Three studies reported on amputation, with one finding a significant increase risk. No increased risk for either outcome was found when compared with active controls. Subgroup analysis did show an increased risk of UTI with dapagliflozin only (RR 1.21; 95% CI 1.02 to 1.43, I2=0.0%), but no other analysis supported an increased risk of AKI, DKA, UTI or fracture.Conclusions Current evidence from RCTs does not suggest an increased risk of harm with SGLT2 inhibitors as a class over placebo or active comparators with respect to AKI, DKA, UTI or fracture. However, wide CIs for many comparisons suggest limited precision, and therefore clinically important adverse events cannot be ruled out. Dapagliflozin, appears to independently increase the risk of UTI, although the mechanism for this intraclass variation in risk is unclear.PROSPERO registration number CRD42016038715. |
| format | Article |
| id | doaj-art-60be73cc49654bb199711c7ee0033113 |
| institution | Kabale University |
| issn | 2044-6055 |
| language | English |
| publishDate | 2019-02-01 |
| publisher | BMJ Publishing Group |
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| series | BMJ Open |
| spelling | doaj-art-60be73cc49654bb199711c7ee00331132025-02-06T19:35:09ZengBMJ Publishing GroupBMJ Open2044-60552019-02-019110.1136/bmjopen-2018-022577Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysisKris Aubrey-Bassler0John-Michael Gamble1Jennifer R Donnan2Catherine A Grandy3Eugene Chibrikov4Carlo A Marra5Karissa Johnston6Michelle Swab7Jenna Hache8Daniel Curnew9Hai Nguyen10Primary Healthcare Research Unit, Memorial University of Newfoundland, St. John`s, Newfoundland, CanadaSchool of Pharmacy, University of Waterloo, Kitchener, Ontario, CanadaPharmacy, Memorial University of Newfoundland, St. John`s, Newfoundland and Labrador, Canada1 School of Pharmacy, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada1 School of Pharmacy, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada1 School of Pharmacy, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, CanadaBroadstreet HEOR, Vancouver, British Columbia, CanadaHealth Sciences Library, Faculty of Medicine, Memorial University of Newfoundland, St. John`s, Newfoundland, Canada1 School of Pharmacy, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada1 School of Pharmacy, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, CanadaHealth Service and Population Research Department, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United KingdomObjective To estimate the association between the use of sodium glucose co-transporter-2 (SGLT2) inhibitors and postmarket harms as identified by drug regulatory agencies.Design We conducted a systematic review and meta-analysis of randomised controlled trials (RCT). Six large databases were searched from inception to May 2018. Random effects models were used to estimate pooled relative risks (RRs).Intervention SGLT2 inhibitors, compared with placebo or active comparators.Primary outcomes Acute kidney injury (AKI), diabetic ketoacidosis (DKA), urinary tract infections (UTI), bone fractures and lower limb amputations.Results We screened 2418 citations of which 109 were included. Most studies included one of four SGLT2 inhibitors, dapagliflozin, canagliflozin, empagliflozin and ipragliflozin. When compared with placebo, SGLT2 inhibitors were found to be significantly protective against AKI (RR=0.59; 95% CI 0.39 to 0.89; I2=0.0%), while no difference was found for DKA (RR 0.66; 95% CI 0.30 to 1.45, I2=0.0%), UTI (RR 1.02; 95% CI 0.95 to 1.09, I2=0.0%) or bone fracture (RR 0.87; 95% CI 0.69 to 1.09, I2=1.3%). Three studies reported on amputation, with one finding a significant increase risk. No increased risk for either outcome was found when compared with active controls. Subgroup analysis did show an increased risk of UTI with dapagliflozin only (RR 1.21; 95% CI 1.02 to 1.43, I2=0.0%), but no other analysis supported an increased risk of AKI, DKA, UTI or fracture.Conclusions Current evidence from RCTs does not suggest an increased risk of harm with SGLT2 inhibitors as a class over placebo or active comparators with respect to AKI, DKA, UTI or fracture. However, wide CIs for many comparisons suggest limited precision, and therefore clinically important adverse events cannot be ruled out. Dapagliflozin, appears to independently increase the risk of UTI, although the mechanism for this intraclass variation in risk is unclear.PROSPERO registration number CRD42016038715.https://bmjopen.bmj.com/content/9/1/e022577.full |
| spellingShingle | Kris Aubrey-Bassler John-Michael Gamble Jennifer R Donnan Catherine A Grandy Eugene Chibrikov Carlo A Marra Karissa Johnston Michelle Swab Jenna Hache Daniel Curnew Hai Nguyen Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis BMJ Open |
| title | Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis |
| title_full | Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis |
| title_fullStr | Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis |
| title_full_unstemmed | Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis |
| title_short | Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis |
| title_sort | comparative safety of the sodium glucose co transporter 2 sglt2 inhibitors a systematic review and meta analysis |
| url | https://bmjopen.bmj.com/content/9/1/e022577.full |
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