It is unclear whether SGLT2i show reduction in mortality in all patients with type 2 or just in patients with type 2 diabetes with increased cardiovascular risk.
Recent observational studies have shown a tremendously lower rate of death when patients used sodium-glucose cotransporter 2 inhibitor (SGLT2i) compared to other classes of medications in patients with type 2 diabetes. These findings found that this mortality benefit of SGLT2i applied to all patients with type 2 diabetes and not only to patients with increased cardiovascular risk. The results of two randomized trials found that there was as high as >50% lower rates of mortality as well as a lower incidence of major cardiovascular events when type 2 diabetes patients were using SGLT2i.
The Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL) is an observational study using health care data from many different countries, including Norway, Denmark, Sweden, Germany, the U.K., and the U.S. In this study, patients who were started on SGLT2i between November 2012 and November 2016 were compared to patients with other glucose-lowering drugs (oGLD) during the same time period. Enrolled patients were followed from the initiation of treatment until the end of the treatment, death or end of data availability. In this study, a total of 166,033 new SGLT2i and 1,226, 221 oGLD users were identified. The death rate of SGLT2i group vs oGLD group was 5.2 per 1,000 person years compared to 12.4 per 1,000 person years, respectively. The results found that patients using SGLT2i had 51% lower rate of death than oGLD group (p<0.001).
Another observational study by Thomas Nystrom et al. used data from Sweden and studied patients who used SGLT2i, DPP4i, or insulin between July 1, 2013 and December 31, 2014. Patients in this study were followed from first prescription in that period until the end of the treatment, death, or end of the study period. In this study, a total of 12,544 SGLT2i/DPP4i users and 25,059 insulin users were studied. The death incidence rate of SGLT2i/DPP4i group vs insulin group was 25.6 per 1,000 person-years compared to 45.7 per 1,000 person years, respectively. This study concluded that use of SGLT2i/DPP4i had 44% lower death rate compared to insulin (p<0.001).
The mortality rate in the SGLT2i in CVD-REAL study is much lower than in the Swedish study (5.2 vs 25.6 per 1,000 person- years, respectively). These differences in results could be due to potential bias in the study. Authors believe that there might be some incompleteness of death information in the U.S. database. In addition, there might also be variation on prescribing access to newer drugs like SGLT2i between different countries. Many other factors such as patients’ health behavior like diet and exercise or patients’ overall health status can influence the results.
Despite these bias, the results of the two observational studies discussed here can be compatible with reported results of the EMPA-REG OUTCOME randomized trial, which showed a 32% reduction in mortality in patients using empagliflozin (SGLT2i). However, this trial included patients with type 2 diabetes at increased risk of cardiovascular disease and it was shown that empagliflozin has specific cardiovascular effects. If we assumed that impact on mortality is greater for patients with cardiovascular disease, than it can be hypothesized that the 32% reduction in mortality would be lower in broader population with diabetes. This statement can be supported by the recent Canagliflozin cardiovascular assessment study (CANVAS) randomized trial. Results of CANVAS study showed that there was a 13% reduction in death for SGLT2i group compared to placebo group in patients with type 2 diabetes. In the CANVAS trial population, only 66% patients had cardiovascular disease compared to EMPA-REG outcome trial where all patients had cardiovascular disease.
In conclusion, the >50% lower risk of death that is reported by two observational studies discussed here of SGLT2i is not consistent with reductions found in recent large randomized trial of SGLT2i. These findings may be due to potential bias of the studies that were not taken into consideration when results were reported. Furthermore, it is still uncertain whether the significant reduction shown with empagliflozin also applies to other drugs of SGLT2i class and whether the results apply to all patients with type 2 diabetes or just the patients with increased cardiovascular risk.
- Two observational studies showed as high as >50% reduction in mortality in patients using SGLT2i compared to other class of medications in type 2 diabetes patients.
- It is uncertain whether the reduction in death is due to empagliflozin or if this applies to all drugs of the SGLT2i class.
- The results of this study cannot be generalized for all patients with type 2 diabetes. Further studies need to conducted to conclude whether reduction in mortality is just in increased cardiovascular risk patients with type 2 diabetes or if it applies to all people with type 2 diabetes.
Suissa, S. Lower risk of death with SGLT2 Inhibitors in Observational studies: Real or Bias? Diabetes Care. 2018; 41:6-10.
Vidhi Patel, Pharm. D. Candidate 2018, LECOM School of Pharmacy