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Real-World Data on the Benefit of Sodium Glucose Cotransporter 2 Inhibitors in Reducing Cardiovascular Risk

Jan 5, 2021
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Abdullah Al-Ajmi, PharmD Candidate, Skaggs School of Pharmacy and Pharmaceutical Sciences

 SGLT2 inhibitors compared to DPP-4 inhibitors: which showed a favorable effect on MACE? 

Many studies have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective in reducing major adverse cardiovascular events (MACE) when compared to placebo in patients with type 2 diabetes (T2DM). One study looked at the effect of empagliflozin in reducing MACE when compared to placebo. It showed that empagliflozin significantly decreased MACE and hospitalization related to cardiovascular disease compared to placebo. Similarly, another study showed that canagliflozin had similar outcomes compared to placebo. However, not many studies have reported this outcome when compared to other treatments for T2DM. Furthermore, the previous studies were carried out in a controlled setting, which may not reflect real-life use of these drugs; thus, the results’ generalizability may be limited. 


Therefore, this study was designed to address the previous limitations. It aimed to compare SGLT2 inhibitors with dipeptidyl peptidase-4 (DPP-4) inhibitors in terms of their MACE risk reduction in patients with T2DM. The study was carried out retrospectively. The data were collected from sites in Canada and the U.K., including hospital admissions, prescribed drugs, and doctors’ notes. The data was gathered from January 2006 to June 2018 for patients who received any antidiabetic drug from all approved treatments, out of which prescriptions with SGLT2 inhibitor or DPP-4 inhibitors were included in the study cohort. The study included patients from ≥18 years; however, in Alberta, they included patients who are ≥19 years, while in Ontario, they included patients ≥66 years old. They excluded patients with less than 365 days of treatment follow-up, patients who received SGLT2 and DPP-4 inhibitors on the same date or before starting the study date. Follow-up was continued until the treatment is discontinued for any reason. The study identified MACE or MACE related mortality as a primary outcome. Additionally, all-cause mortality and cardiovascular-related hospital admission were identified as secondary outcomes. 

The study included around 270,902 patients matched at a 1:1 ratio from the SGLT2 inhibitors and DPP-4 inhibitors groups. The basic patients’ characteristics were similar between the groups. The SGLT2 inhibitors used included canagliflozin (42.3%), dapagliflozin (30.7%), and empagliflozin (27%). The DDP-4 inhibitors used included alogliptin, linagliptin, saxagliptin, and sitagliptin. Vildagliptin was only available in the cohort from the U.K. With an average follow-up of 0.9 years, the results showed that MACE reduced with SGLT2 inhibitors seen in 2146 reported events compared to the DPP-4 3001 reported events, hazard ratio 0.76 (95% CI, 0.69-0.84). Similarly, there was a significant decrease in the rates of myocardial infarction and mortality related to cardiovascular disease, HR 0.82 (95% CI, 0.70-0.96) and 0.60 (95% CI, 0.54-0.67), respectively. Simultaneously, there was a nonsignificant reduction in ischemic strokes reduction of HR 0.85 (95% CI, 0.72-1.01). In the secondary outcomes, SGLT2 inhibitors showed a reduction in all-cause mortality HR 0.60 (95% CI, 0.54-0.67) and cardiovascular-related hospital admissions HR 0.43 (95% CI 0.37-0.51). The results were not affected by patient parameters, such as age and sex. It was also similar between different SGLT2 inhibitors, canagliflozin, dapagliflozin, and empagliflozin. Moreover, prior insulin use did not affect the results.  

One of the study’s strengths is the large number of study populations, studying multiple SGLT2 inhibitor drugs as described in the study. On the other hand, the design of the study is considered a limitation. Since it was an observational study, there is room for selection bias and other confounding variables that can affect the outcomes. Although the author stated that efforts had been put in place to reduce the risk of confounding results, they cannot be completely ruled out. Additionally, due to the study algorithm used to define outcomes, misclassification of outcomes is possible. Also, the study follow-up window was small; thus, the result may not represent long-term use. This indicates that there is room for further research in the long-term effect of SGLT2 inhibitors on MACE reduction in real-life use.  

Practice Pearls: 

  • Compared to DPP-4 inhibitors, SGLT2 inhibitors showed reduced MACE risk in patients with T2DM. 
  • A significant benefit of SGLT2 inhibitors was reported in all-cause mortality and myocardial infarction but not in ischemic stroke.   
  • Similar results were reported with different SGLT2 inhibitors. 


Filion, Kristian B et al. “Sodium Glucose Cotransporter 2 Inhibitors And Risk Of Major Adverse Cardiovascular Events: Multi-Database Retrospective Cohort Study”. BMJ, 2020, p. m3342. BMJ, doi:10.1136/BMJ.m3342. Accessed 5 Nov 2020. 

Zinman, Bernard et al. “Empagliflozin, Cardiovascular Outcomes, And Mortality In Type 2 Diabetes”. New England Journal of Medicine, vol 373, no. 22, 2015, pp., 2117-2128. Massachusetts Medical Society, doi:10.1056/nejmoa1504720. Accessed 5 Nov 2020. 


Abdullah Al-Ajmi, PharmD Candidate, Skaggs School of Pharmacy and Pharmaceutical Sciences  



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