Emulation trials in SLE: Real or Fake? Save

Recently a landmark paper was published in A&R studying the results of an emulation trial (1). My colleagues and I were able to write an editorial on this paper and describe emulation trials (2).

What: SGLT2i (sodium-glucose co-transporter 2 inhibitors) show benefit in SLE patients with diabetes mellitus (DM), for both renal protection and reducing cardiovascular events, using data from an American large insurance claim database (1).

Who:  2,165 SLE patients with T2DM in a large insurance database who were receiving either SGLT2i (i.e. canagliflozin, dapagliflozin, empagliflozin and ertugliflozin) or 2,165 SLE patients who were propensity score matched patients who received a dipeptidyl peptidase 4 inhibitor (DPP4i, i.e. sitagliptin, saxagliptin, linagliptin, and alogliptin). These patients were matched on multiple parameters beyond age and sex.

How: SGLT2is, for prevention of renal and cardiovascular outcomes in patients with systemic lupus erythematosus (SLE) and type 2 diabetes mellitus (T2DM), using data from an American insurance-based population.

Propensity score matching a technique used in observational studies which estimates treatment effect (3). This is done by balancing groups (such as an intervention and control group or groups with the same disease receiving different treatments).  Each person’s propensity score is her/his probability of receiving a specific treatment based on some characteristics (ex. age, sex, disease duration, severity of disease, etc). Then people with similar propensity scores are matched who received the comparison treatment. This balance can decrease bias but is not the same as randomization where known and unknown factors should be equally balanced between groups.

A target emulation trial uses observational data to mimic the design and principles of a hypothetical randomized controlled trial (RCT) (4,5), which uses existing data to estimate the causal effect of an intervention in a way that tries to mirror the rigor of a real randomized trial.

So there have been many emulation trials and the one of interest demonstrated that SGLT2i reduced both renal and CV events in SLE patients with DM vs. the older Rx with DPP4i. 

The issues are:

Is this true in non-diabetic patients?

Are these the same results compared to if an actual RCT was done (or is the effect overestimated, or less likely underestimated as there are prescribing biases (channeling bias) as the newer drugs are prescribed far more now? I am uncertain if there is an interaction between SLE and DM that allows for a specific effect vs. if no SLE and only type2 DM where these protective factors in renal and CV has already been demonstrated.

So are emulation trials real or fake? I don’t know! But I believe that SGLT2i have value in SLE patients with or without nephritis but it may be currently a leap of faith.

References

1. Ma KS, Lo JE, Kyttaris VC, Tsokos GC, Costenbader KH. Efficacy and Safety of Sodium-Glucose Cotransporter 2 Inhibitors for the Primary Prevention of Cardiovascular, Renal Events, and Safety Outcomes in Patients With Systemic Lupus Erythematosus and Comorbid Type 2 Diabetes: A Population-Based Target Trial Emulation. Arthritis Rheumatol. 2025 Apr;77(4):414-422. doi: 10.1002/art.43037. Epub 2024 Dec 5. PMID: 39431397.
2. Pope J, Keracabeyli D, Aviña-Zubieta A. Target trial emulations of SGLT2 inhibitors show benefit in SLE!
3. Propensity Score Matching - Dimewiki.
4. Hernán MA, Robins JM. Using big data to emulate a target trial when a randomized trial is not available. Am J Epidemiol. 2016;183:758-64. DOI: 10.1093/aje/kwv254.
5. Labrecque JA, Swanson SA. Target trial emulation: teaching epidemiology and beyond. Eur J Epidemiol. 2017;32:473-5. DOI: 10.1007/s10654-017-0293-4.