Examining the evidence to date on whether sodium-glucose transporter 2 inhibitors (SGLT2 inhibitors) reduce mortality.
Many studies looked at the effect of sodium-glucose transporter 2 inhibitors in improving cardiovascular risk, providing renal protection, and reducing all-cause mortality. One study showed that empagliflozin effectively reduced the mortality from any cause by 32% in patients with type 2 diabetes (T2D). On the other hand, other studies that included other SGLT2 inhibitors did not reduce mortality. For instance, one study showed that sotagliflozin was not associated with a significant decrease in all-cause mortality versus placebo. These findings indicate that there is a difference in mortality outcomes between the different SGLT2 inhibitors.
This study aimed to review and assess all the current evidence regarding SGLT2 inhibitors and their impact on all-cause mortality.
The study included all randomized controlled trials about SGLT2 inhibitors carried out on humans until September 2020. It also included trials that were pending publication. It included trials with a minimum period of 53 weeks, that had more than 100 participants, and a placebo-controlled or active-controlled design. It excluded studies with <100 participants per group since they may have impacted the strengths of results. It also included only trials on drugs and doses that were approved by the FDA or EMA. Outcomes extracted were data on mortality, primary outcomes from each trial, estimated glomerular filtration rate (eGFR), age, A1C, BMI, and systolic blood pressure (SBP).
The primary outcome was the all-cause mortality of the studied drug compared to drug or placebo. The odds ratio (OR) was used to assess all-cause mortality, with a 95% confidence interval (95% CI). The study included data from 21 trials that met the inclusion criteria. The total number of patients was 39,593 on SGLT2 inhibitors and 30,771 on placebo/or comparator. The average study duration was around 104 weeks. Out of the 21 trials, one study had zero mortalities; thus, it was excluded.
The analysis showed that SGLT2 inhibitors had a significantly lower rate of all-cause mortality (OR 0.86, 95% CI, 0.81-0.91, P<0.00001). Also, with a random-effects model, results showed that SGLT2 inhibitors significantly reduced all-cause mortality (OR 0.85, 95% CI, 0.80-0.91, P<0.00001). Low heterogeneity was reported with these results I2=17%. When trials that had <100 deaths were excluded, a significant reduction in mortality was reported with empagliflozin, dapagliflozin, and canagliflozin (OR 0.85, 95% CI, 0.81-0.91, P<0.00001, I2=46%). In contrast, ertugliflozin did not significantly affect all-cause mortality reduction when trials with <100 deaths were excluded. Overall, the difference between SGLT2 inhibitors regarding all-cause mortality did not show statistical significance.
The study found that there was no direct association between the outcomes and patent- specific characteristics. These include age, A1C, gender, BMI, eGFR, and SBP. Additionally, there was no association with the number of African (or African-American) participants, A1C reduction rate by the end of the study, and a history of cardiovascular events. The only direct association was found in the Asian population (P=0.37). On the other hand, Caucasian patients have had an inverse association with the outcomes (P=0.016).
The study showed that SGLT2 inhibitors were linked with a significant reduction in all-cause mortality. Also, the study showed that there was no significant difference between the different SGLT2 inhibitor drugs. It indicates that this outcome may be considered a class effect. Additionally, the findings showed that the more the Asian population was included, the higher the reduction in all-cause mortality. The opposite was reported with Caucasian populations in which a lower proportion was linked with lower mortality. At the same time, other parameters did not affect the outcomes. The study did not show publication bias. One of the study’s limitations is that the findings may not be conclusive since they are based on trials designed for other primary endpoints. The all-cause mortality was a secondary endpoint in most of the trials. It indicates that the studies may not have been powered sufficiently to identify statistical significance regarding all-cause mortality. Further studies with sufficient power may provide additional supporting evidence to the current outcomes.
- SGLT2 inhibitors were associated with a reduction in all-cause mortality.
- A nonsignificant difference was reported between the different SGLT2 inhibitors.
- Most patient parameters did not change the outcomes except for Asian and Caucasian ethnicities.
Antonio, Silverii Giovanni et al. “SGLT2 inhibitors and all-cause mortality: a meta-analysis of randomized controlled trials.“ Diabetes, obesity & metabolism, 10.1111/dom.14286. 7 Dec. 2020, doi:10.1111/dom.14286. Accessed December 8, 2020. Available from: https://dom-pubs.onlinelibrary.wiley.com/doi/abs/10.1111/dom.14286?af=R
Bhatt, Deepak L. et al. “Sotagliflozin In Patients With Diabetes And Chronic Kidney Disease.” New England Journal Of Medicine, 2020. Massachusetts Medical Society, doi:10.1056/nejmoa2030186. Accessed December 7, 2020. Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa2030186
Abdullah Al-Ajmi, PharmD Candidate, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences