1.
Sodium/Glucose Cotransporter 2 Inhibitors and the Risk of Diabetic Ketoacidosis: An Example of Complementary Evidence for Rare Adverse Events.
Alkabbani, W, Pelletier, R, Gamble, JM
American journal of epidemiology. 2021;(8):1572-1581
Abstract
Evidence from observational studies may be considered complementary to that of randomized controlled trials (RCTs), particularly when assessing rare outcomes of drug therapies. Sodium/glucose cotransporter 2 (SGLT-2) inhibitors are a novel class of antidiabetic agents that have been linked to an increased risk of diabetic ketoacidosis (DKA). We conducted a systematic review and separately meta-analyzed data from RCTs (n = 18; 2013-2019) and cohort studies (n = 7; 2017-2020) to assess the consistency of the magnitude of association between SGLT-2 inhibitors and DKA risk. We illustrate the strengths and weaknesses of the 2 designs. Results from RCTs and observational studies consistently showed almost a doubling in the risk of DKA among patients using an SGLT-2 inhibitor as compared with placebo or an active comparator. In a random-effects model, the pooled relative risk was 2.08 (95% confidence interval (CI): 1.28, 3.40) from placebo-controlled RCTs and 0.82 (95% CI: 0.25, 2.68) from active-comparator RCTs. The pooled adjusted hazard ratio from observational studies was 1.74 (95% CI: 1.28, 2.38). Notably, the 2 designs complement each other in several domains, including external and internal validity and power. This demonstrates a need for more comprehensive evidence when assessing rare adverse events for both sources.
2.
Effectiveness of ketoacidosis prevention campaigns at diagnosis of type 1 diabetes in children: A systematic review and meta-analysis.
Cherubini, V, Marino, M, Carle, F, Zagaroli, L, Bowers, R, Gesuita, R
Diabetes research and clinical practice. 2021;:108838
Abstract
AIM: To determine if diabetes awareness campaigns are an effective intervention to reduce diabetes ketoacidosis at diagnosis of type 1 diabetes in children and youth. METHODS Search strategies included PubMed, Scopus, CINAHL and WOS electronic databases, hand search of select journals and a grey literature search "Google" search to include all relevant information. Studies included community-based interventions focused on children younger than 18 years old. The difference in the frequency of DKA was measured in two separate comparisons; before and after perform awareness campaigns in the same area, and between areas with and without intervention campaigns. RESULTS Of 1136 records identified, 14 studies were eligible for the analysis. The first group of 12 studies measured DKA at diagnosis, before (n = 6548 individuals) and after (n = 4931 individuals) the awareness campaigns. The pooled difference was a reduction of 7.20% (95%CI: 0.99-13.41). The second group of four studies measured the difference in an area with no intervention (n = 338 individuals) and in an area with an awareness campaign (n = 187 individuals). The pooled difference in DKA was 35.71% (95%CI: 5.81-65.61). CONCLUSIONS This review demonstrated that DKA awareness campaigns are effective to reduce DKA among children and adolescents with type 1 diabetes and the core components that explain why these campaigns are effective. Back to top.
3.
Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis.
Donnan, JR, Grandy, CA, Chibrikov, E, Marra, CA, Aubrey-Bassler, K, Johnston, K, Swab, M, Hache, J, Curnew, D, Nguyen, H, et al
BMJ open. 2019;(1):e022577
Abstract
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.