Clinical Adverse Events of High-Dose vs Low-Dose Sodium–Glucose Cotransporter 2 Inhibitors in Type 2 Diabetes

A Meta-Analysis of 51 Randomized Clinical Trials

Fang-Hong Shi; Hao Li; Jiang Yue; Yi-Hong Jiang; Zhi-Chun Gu; Jing Ma; Hou-Wen Lin


J Clin Endocrinol Metab. 2020;105(11) 

In This Article

Abstract and Introduction


Aims: The aims of this work are to assess the clinical adverse events (AEs) of high-dose vs low-dose sodium–glucose cotransporter 2 inhibitors (SGLT2 inhibitors) in patients with type 2 diabetes mellitus (T2DM).

Methods: We searched MEDLINE, EMBASE, and Cochrane Library from January 1, 2006 to March 10, 2020, for identifying eligible randomized clinical trials (RCTs) that reported AEs by high-dose and low-dose SGLT2 inhibitors in T2DM patients. Random-effects models was used to obtain summary relative risks (RRs) with associated 95% CIs. Prespecified subgroup analyses according to individual SGLT2 inhibitors and follow-up duration, and leave-one-out sensitivity analysis were conducted.

Results: A total of 51 RCTs involving 24 371 patients (12 208 received high-dose and 12 163 received low-dose SGLT2 inhibitors) were included. Overall, the heterogeneity among included studies was relatively low (I 2 < 50% for each outcome). No significant differences between high-dose and low-dose SGLT2 inhibitors were observed for overall safety (including any AEs, serious AEs, AEs leading to discontinuation, and death) and specified safety (including infections and infestations, musculoskeletal disorders, gastrointestinal disorders, osmotic diuresis-related AEs, volume-related AEs, renal-related AEs, and metabolism and nutrition), except for a mild increase in risk for AEs related to study drugs (RR: 1.08; 95% CI, 1.01–1.16) that mainly derived from canagliflozin (RR: 1.17; 95% CI, 1.05–1.30). Subgroup analyses were consistent with the primary outcomes.

Conclusions: This study provided substantial evidence that AEs of SGLT2 inhibitors were not dose related.


Diabetes mellitus is estimated to affect more than 415 million people worldwide, and type 2 diabetes mellitus accounts for more than 90%.[1] American Diabetes Association guidelines in 2020 recommended metformin as the first-line therapy for type 2 diabetic patients.[2] Recently, for type 2 diabetic patients with cardiovascular diseases, sodium–glucose cotransporter 2 inhibitors (SGLT2 inhibitors) have been regarded as the initial treatment according to the guidelines of the European Society of Cardiology and the European Association for the Study of Diabetes.[3]

SGLT2 inhibitors, as a novel class of antidiabetic drugs, can reduce the reabsorption of renal tubular glucose and subsequently cause the excretion of urine glucose.[4] SGLT2 inhibitors have favorable effects on blood glucose control as well as cardiovascular and renal benefits;[5] however, certain safety issues, such as infection-related[6–8] and renal-related adverse events (AEs),[9–11] have been raised with the extensive clinical application of SGLT2 inhibitors. The US Food and Drug Administration (FDA) has published a series of safety communications, including the risk of necrotizing fasciitis with all SGLT2 inhibitors; risk of serious urinary tract infections, ketoacidosis, and acute kidney injury related to canagliflozin and dapagliflozin; risk of leg/foot amputations; and bone fractures associated with canagliflozin.[12–16] Our previous meta-analysis has given a comprehensive picture of the overall noncardiovascular safety of SGLT2 inhibitors. It validated the FDA safety alerts and detected additional safety issues including osmotic diuresis-related AEs, volume-related AEs, and hypoglycemia,[17] but we did not assess the association of AEs with different dosages of SGLT2 inhibitors. To date only 2 meta-analyses have evaluated certain AEs on low- and high-dose of canagliflozin and empagliflozin.[18,19] But these studies did not concern the overall safety of all approved SGLT2 inhibitors. Therefore, we aimed to summarize all approved SGLT2 inhibitors from randomized clinical trials (RCTs) for a comprehensive AEs evaluation of SGLT2 inhibitors at high and low doses.