Sodium/Glucose Cotransporter 2 Inhibitors and the Risk of Diabetic Ketoacidosis

An Example of Complementary Evidence for Rare Adverse Events

Wajd Alkabbani; Ryan Pelletier; John-Michael Gamble


Am J Epidemiol. 2021;190(8):1572-1581. 

In This Article

Abstract and Introduction


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.


Randomized controlled trials (RCTs) are considered the gold standard of clinical evidence, due to the role of randomization in causal inference.[1] Nonetheless, there has been much development over recent years of methods used in observational drug-effect studies, much of which has focused on causal inference.[2] Despite infamous examples of conflicting findings,[3,4] observational studies are argued to provide complementary evidence when RCTs are impossible (due to ethical and/or legal considerations), inadequate (low external validity, irrelevant comparisons), or inappropriate (a rare outcome, long-follow-up required).[5,6]

Studying rare adverse effects of drug therapies is one scenario wherein evidence from observational studies complements that from RCTs. A contemporary example is that of the risk of diabetic ketoacidosis (DKA). In 2015, the Food and Drug Administration published drug safety communications warning that a new class of diabetes therapies called sodium/glucose cotransporter 2 (SGLT-2) inhibitors may lead to DKA,[7] albeit with an atypical presentation whereby not all cases involved hyperglycemia but rather some involved euglycemia.[8] Herein, using this timely and clinically relevant example, we assess the consistency of the magnitude of association of SGLT-2 inhibitor exposure with DKA between pooled data from randomized clinical trials and pooled data from observational studies. We also illustrate how strengths and weaknesses of the 2 evidentiary sources are ameliorative in multiple domains, specifically when RCTs have insufficient power and suboptimal adjudication of events.