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Benefits of SGLT2 Inhibitors in Patients With or Without History of CVD

Jul 21, 2018

Investigators analyze CVD-REAL study to determine impact of drug class on patients with T2D and HF history.

Type 2 diabetes (T2D) comes with a whole host of problems. One major concern is the inherent increased cardiovascular risk. Many studies to date have been performed to establish which antidiabetic medications are best for those with a history of cardiovascular disease (CVD). At the moment, data has shown that people with diabetes and concomitant CVD can experience benefit when sodium-glucose co-transporter 2 (SGLT2) inhibitors are added to their regimens. Trials like EMPA-REG OUTCOME and CANVAS have shown that patients with T2D, with or without baseline CVD, receiving SGLT2 inhibitors are at reduced risk for various cardiovascular outcomes (i.e. cardiovascular death, myocardial infarction, stroke, etc.).


CVD-REAL, a large observational study, assessed over 300,000 patients with T2D initiated on SGLT2 inhibitors. This study found SGLT2 inhibitor use showed lower risk of death and heart failure (HF) compared to the use of other antidiabetic medications. But one component this study did not note was if there was a difference in rates of death or HF in patients with a history of CVD. Therefore, the objective of the investigators was to perform an analysis on the CVD-REAL study in the hopes of determining if the presence or absence of CVD has an impact on CVD outcomes (i.e. death or HF) when SGLT2 inhibitors are initiated in patients with T2D.

Data from the previous trial was obtained through each country’s (i.e. United States, United Kingdom, Sweden, Norway, and Denmark) respective medical records, electronic health records, and the like. Patients included in the study were adults with both T2D diagnosis and ≥ 1 year of historical data. Individuals with either type 1 diabetes or gestational diabetes were not enrolled in the study. Patients were matched (1:1) and placed into one treatment group, which were as follows: 1) SGLT2 inhibitor – previously on medication or recently initiated, 2) other antidiabetic medications and no history of SGLT2 inhibitor use within previous year. For the purposes of analysis, patients were stratified based on their history of CVD when the therapies were initiated. CVD history included: acute myocardial infarction, stroke, HF, unstable angina, transient ischemic attack, coronary revascularization, or occlusive peripheral artery disease.

Overall, the study included 306,156 patients who were evenly distributed into either treatment group. Baseline characteristics were evenly matched based on treatment type and CVD history. Most patients did not have CVD history (12.8% CVD history, 3.0% HF history). Breaking down the SGLT2 inhibitor treatment group showed the following: 1) 53.2% treated with canagliflozin, 2) 41.4% treated with dapagliflozin, 3) 5.4% treated with empagliflozin. SGLT2 inhibitor trends showed that canagliflozin was mainly used in the U.S. (75.9%) while dapagliflozin was heavily used in the European countries (92.2%) included in the study (p < 0.001). The final SGLT2 inhibitor used in the study, empagliflozin, was not often used in the U.S. and Europe. Analysis of the other treatment group, those receiving other antidiabetic medications, showed the following: 33.7% treated with insulin, 17.3% treated with dipeptidyl peptidase-4 inhibitors, 17.1% treated with sulfonylureas, 13.8% treated with glucagon-like peptide-1 receptor agonists, and lastly 11.4% treated with metformin.

Patients included in the study were followed from the start of either treatment until they experienced a cardiovascular event. The average follow-up time for SGLT2 inhibitor group was 313-387 days while those treated with other antidiabetic medications were followed for 299-383 days. By the study’s end, 1,871 deaths and 1,586 HF events occurred. The results of the death and HF rates based on CVD history can be found in Table 1: Death/HF Rate in Patients with Variable CVD History. The results for event rates in patients with or without CVD after treatment with either SGLT2 inhibitors or other antidiabetic medications are located in Table 2: Event Rates After Initiation of Treatment in Patient with Variable CVD History.

Table 1: Death/HF Rate in Patients with Variable CVD History
CV Outcome CVD History Result
Death Rate With CVD 2.7 per 100 person years
Without CVD 0.7 per 100 person years
HF Rate With CVD 2.7 per 100 patient years
Without CVD 0.2 per 100 patient years
Table 2: Event Rates After Initiation of Treatment in Patients with Variable CVD History
Treatment CV Outcome CVD History Result

(Event rate per 100 patient-years)

HR (95% CI)


Death Established CVD 1.8 0.56 (0.44-0.70)
HF 2.3 0.72 (0.63-0.82)
Death or HF 4.0 0.63 (0.57-0.70)
Other Antidiabetic Medication Death Established CVD 3.6 N/A
HF 3.2
Death or HF 6.7


Death No CVD 0.5 0.56 (0.50-0.63)
HF 0.1 0.61 (0.48-0.78)
Death or HF 0.6 0.56 (0.50-0.62)
Other Antidiabetic Medication Death No CVD 0.9 N/A
HF 0.2
Death or HF 1.1

All in all, the results showed that death and HF rates were overall higher in patients with CVD history compared to those without. Patients receiving SGLT2 inhibitors, regardless of CVD history, were found to have lower rates of death or HF compared to those treated with other antidiabetic medications. These trends remained consistent even after combining the outcomes; risk for the composite endpoint (i.e. death + HF) was lower in the group treated with SGLT2.

Cavender, et al was able to show that patients with T2D with or without cardiovascular history can benefit from the SGLT2 inhibitor treatment. Furthermore, a result of considerable importance is the association noted in patients with HF. This observational analysis of the CVD-REAL trial was able to confirm that use of SGLT2 inhibitors in a T2D patient with a history of HF is especially beneficial.

A strength of this study lies in the number of participants enrolled and the geographic variety. Investigators consistently found associations between CVD outcomes and SGLT2 inhibitor use in each country studied, a finding that was supported by a lack of geographic heterogeneity across all associations. Finally, although the findings were substantial, the study’s limitations should be mentioned. They are as follows: 1) observational study design, 2) confounding despite implementing propensity-matching, 3) despite lengthy follow-up, it is unknown if the association between SGLT2 inhibitor use and CVD outcomes is sustainable, 4) incomplete mortality data obtained from the United States.

Practice Pearls:

  • Patients with T2D, with or without a history of CVD, treated with SGLT2 inhibitors showed lower risk of death and HF.
  • Other antidiabetic medications studied in the CVD-REAL trial (i.e. insulin, GLP-1-agonists, metformin, etc.) showed higher risk of death or HF.
  • The results of this study suggest SGLT2 inhibitors can be beneficial for not only those with established cardiovascular disease, but those without current CVD history.


Cavender, M., Norhammar, A., Birkeland, K., Jorgensen, M., Wilding, J., Khunti, K., Fu, A., Bodegard, J., Blak, B., Wittbrodt, E., Thuresson, M., Fenici, P., Hammar, N., Kosiborod, M. et al. SGLT-2 Inhibitors and Cardiovascular Risk. Journal of the American College of Cardiology. 71.22 (2018): 2497-2506. DOI: 10.1016/j.jacc.2018.01.085.

Kaytie A. Weierstahl, Pharm.D. Candidate, LECOM School of Pharmacy