Comprehensive Analysis of Adverse Events Associated With SGLT2is: A Meta-Analysis Involving Nine Large Randomized Trials

Abstract

Recently, Lin and colleagues assessed the safety of sodium-glucose cotransporter 2 inhibitors (SGLT2is) by a meta-analysis [1], in which the authors assessed 16 kinds of adverse events (AE) reported in the published articles based on 10 randomized controlled trials. We conducted a further meta-analysis and targeted the association between use of SGLT2is and occurrences of various kinds of serious AE published in the Clinical Trials website (clinicaltrials.gov). Our meta-analysis revealed that use of SGLT2is was not significantly associated with occurrences of 980 kinds of serious AE but was significantly associated with lower risks of 29 kinds of serious AE, especially including several important respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease, sleep apnoea syndrome, and pneumonia). These findings may cause more studies to evaluate the possibilities of gliflozins being used for prevention of these specific diseases.

SGLT2 Inhibitors in Chronic Kidney Disease: From Mechanisms to Clinical Practice

“…A possible mechanism was found in their insulin-independent reduction in blood glucose and ensuing hyperglucagonemia [ 139 ]. Similar to the previously discussed UTIs, the earlier studies rejected the apparent increased risk for DKA [ 132 ], while the most recent ones heavily reaffirm the risk [ 82 , 135 , 136 , 140 ].…”

“…As previously mentioned, SGLT2i have profound benefits on the cardiovascular system. SGLT2i have been observed to significantly lower the risk of not only renal, but heart failure as well [ 23 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 ], which is not surprising considering the many effects already discussed in this chapter, such as the improvement of blood pressure, reduction in obesity and promotion of vasodilation, all of which have a beneficial effect on ventricular preload and afterload [ 84 ]. However, the most prominent effects of SGLT2i on heart function are independent of the aforementioned cardiovascular risk factors, which is in fact why they were endorsed in the contemporary heart failure guidelines as Class I recommended therapy [ 90 ].…”

“…This view has been confirmed by the following studies in 2019 [ 23 , 130 , 131 , 132 ]; however, one reported that dapagliflozin does increase the risk of UTIs, although the exact mechanism was unclear [ 132 ]. Apart from rare studies, such as a recent one from Borovac et al, which did not find an increased risk of UTIs in a population with heart failure [ 133 ], unfortunately, the most recent meta-analyses paint a different picture, showing an increased risk for UTIs [ 82 , 134 ] that is consistent across all SGLT2 inhibitors [ 135 ], while reaffirming the previously established increased risk for genital and fungal infections [ 71 , 82 , 134 , 135 , 136 ]. While the probable cause for this—the greater flow of glucose through the urinary tract and the genital area—is abundantly clear, the opposite mechanism is probably what explains this interesting finding from a recent study [ 82 ]; SGLT2i are reported to lower the risk for pneumonia, bronchitis and respiratory tract infection, which is potentially caused by their general glucose lowering effect.…”

“…Similar to the previously discussed hypoglycemia, SGLT2i have also been hypothesized to cause hypotension, since one of the main consequences of increased glucose and sodium reabsorption in the proximal tubule is increased diuresis and possible volume depletion. All the recent studies have, to a lesser or greater extent, confirmed that hypothesis, putting the focus on the need to adjust diuretic and/or antihypertensive treatment accordingly [ 23 , 71 , 82 , 129 , 135 , 136 ].…”

Association of adverse respiratory events with sodium-glucose cotransporter 2 inhibitors versus dipeptidyl peptidase 4 inhibitors among patients with type 2 diabetes in South Korea: a nationwide cohort study

“…In contrast, only a small number of studies have investigated the respiratory effects of SGLT2is. Meta-analyses of randomized controlled trials showed that SGLT2is reduce the risk of adverse respiratory events versus placebo, including the risks of respiratory disorders [ 21 ], pneumonia [ 22 ], and respiratory failure [ 23 ], as well as the risk of asthma versus dipeptidyl peptidase-4 inhibitors (DPP4is) [ 24 ]. However, the respiratory effects of SGLT2is compared with other second or third-line antidiabetic drugs remain less well understood, and there is substantial uncertainty regarding the generalizability of trial findings to real-world settings [ 25 ].…”