Communicating emerging risks of SGLT2 inhibitors—timeliness and transparency of medicine regulators

Dear Editor

Recently BMJ reported the “BMJ best practice in Type 2 Diabetes Mellitus 2021, for which we congratulate them for the complete coverage of therapy of this complex disease.

We appreciate that the Authors do not indicate any personal preference, but instead they provide a detailed description of clinical needs and available class of medications. Since at the moment robust evidence in favor of a specific drug class is lacking, a shared decision on which treatment to choose between Physician and Patients is mandatory. Of course personal bias should be avoided and the paper (to which we are referring) by Bahasala et al BMJ 2020; 368: m1107 concerning the communication at regulatory agency level of complications of therapy can help: shared informed decision should pull together not only the high cost of new drugs but also the possible occurrence of several side effects.

Limiting this discussion to SGLT2 inhibitors, the shared decision process should discuss not only the results of CVOT on CV effects of SLGT 2 inhibitors but also how these results translate in clinical practice, making clear not only the relative reduction of CV events observed with reduction of mortality but also the clinical meaning of the absolute numbers of saved lives at patient level.

Looking for instance at the EMPA-REG OUTCOME trial, the primary outcome occurred in 490 of 4687 patients (10.5%) in the pooled empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group. In absolute terms the difference is 1.6%, i.e. after three years 89.5% of the treated patients is free of events vs. 87.9% of the untreated patients. The rates of hospitalization for heart failure are 2.7% and 4.1% (absolute difference 1.4%), respectively; i.e. 97.3% of the treated patients are not hospitalized vs. 95.9 of the untreated patients. The rates of death from cardiovascular causes is 3.7%, vs. 5.9% (absolute difference 2.2%) in the placebo group; i.e. after three years 96.3% of the treated patients is alive; vs 94.1% of the untreated patients. Death from any cause is 5.7% and 8.3% (absolute difference 2.6%), respectively i.e. after three years 94.3% of treated patients is living vs 91.7% of the untreated patients.

Any patients can see that the events are infrequent and the absolute difference in the event probability is quite small. It is out of discussion that this effects sound small and clinically questionable. Weighting cardiovascular benefits and side effects to which Patients are exposed by the use of SGLT2 I (mycotic genital complications, urgency, volume depletion, among others) should be honestly represented and complete.

Finally, yet importantly, it is difficult to explain the reasons of the prescription and prompt the use of a medication whose side effects (polyuria, polydipsia and genital infection) are very similar to the common and more troublesome diabetes symptoms.

References
1) BMJ Best Practice,: type 2 diabetes mellitus in adults, updated 18 jan 2021

2) A Bahasale et All: Communicating emerging risks of SGLT2 inhibitors—timeliness and transparency of medicine regulators, BMJ may 2020;369;m1107

3) Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015 Nov 26; 373(22):2117-28.

4) Beatrice C. Lupsa, Silvio E. Inzucchi: Use of SGLT2 inhibitors in type 2 diabetes: weighing the risks and benefits. Diabetologia (2018) 61:2118–2125