Algorithm Predicts Response to SGLT2, DPP-4 Inhibitors in Diabetes

Mitchel L. Zoler, PhD, for Medscape

November 29, 2021

Key Takeaways

  • Study results have validated that five routinely measured clinical values reliably identified patients with type 2 diabetes who had significantly different A1c responses to two important classes of diabetes drugs.

  • The five measures are baseline A1c, age, body mass index (BMI), renal function (expressed as estimated glomerular filtration rate, eGFR), and serum level of the liver enzyme alanine aminotransferase (ALT).

  • The two drug classes are the sodium-glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase 4 (DPP-4) inhibitors.

  • Running the validated algorithm, available online, predicts the anticipated effect after 6 months of adding treatment with an SGLT2 or DPP-4 inhibitor by their effects on A1c levels, weight loss, and drug discontinuation.

  • Investigators are trying to expand the model to other classes of commonly used diabetes medications.

Why This Matters

  • The findings show how translational precision medicine can help guide improved selection of add-on type 2 diabetes therapies.

  • Validation of the findings using both randomized clinical trial data and an independent sample of data from patients receiving routine care robustly showed the utility of simple clinical features to individualize estimates of the risks and benefits of SGLT2 and DPP-4 inhibitors.

Study Design

  • The researchers derived a regression model for correlates of the primary outcome, change in A1c after the first 6 months of treatment with an SGLT2 or DDP-4 inhibitor. 

  • They also created additional regression models for the outcomes of discontinuation of the index treatment and weight loss.

  • The study population included 26,877 patients with type 2 diabetes in the UK Clinical Practice Research Datalink who began treatment on an SGLT2 or DPP4 inhibitor as a secondary agent, starting during or after 2013.

  • Researchers used data from 14,069 of these patients to derive their model and from 9376 patients to validate it.

  • They also performed additional validation using data from 10,414 patients enrolled in any of 14 trials that randomized patients to an agent from each of these two classes.

Key Results

  • A greater response to DPP-4 inhibitors, but not SGLT2 inhibitors, was associated with older age and longer duration of diabetes.

  • A greater response to SGLT2 inhibitors, and less so to DPP-4 inhibitors, was associated with higher eGFR and ALT levels.

  • Higher BMI was linked with less of a response to DPP4 inhibitors and had no association with response to SGLT2 inhibitors.


  • The study could not evaluate the effects of the two drug classes at the individual patient level, as this is only possible with a cross-over design comparison.

  • The assessment did not consider patient ethnicity.

  • The assessment was limited to A1c outcomes at 6 months and did not consider longer-term cardiovascular and renal outcomes, which agents in the SGLT2 inhibitor class are especially effective at improving.


  • The study received no commercial funding.

  • Some authors have reported financial relationships with several companies outside the scope of the current study.

This is a summary of a preprint research study written by authors primarily based at the University of Exeter, UK, as well as at other UK centers on MedRxiv provided to you by Medscape. This study has not yet been peer-reviewed. The full text of the study can be found on


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