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SGLT-2i Effects on Major Cardiovascular Events and Heart Failure

Jan 11, 2020
Editor: Steve Freed, R.PH., CDE

Author: Nour Salhab, Pharm.D. Candidate, USF College of Pharmacy

The use of SGLT2 inhibitors (SGLT-2i) was associated with reduced risk of any cause of death in patients with or without a history of major cardiovascular disease.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors were studied in patients with type 2 diabetes with a history of cardiovascular disease or with a high cardiovascular risk. These studies have concluded that SGLT-2i reduce the risk of cardiovascular outcomes. However, complementary data is needed to assess the extent of their effectiveness in a broad group of patients. Some observational studies were done; however, these studies had major limitations, such as the use of immortal time. Additionally, adequate data on causes of death and total mortality was lacking. This study aimed to observe patients who were newly prescribed SGLT2 inhibitors to compare with patients who were newly prescribed dipeptidyl peptidase 4 (DPP4) inhibitors.


This cohort was conducted from April 2013 until December 2016 in Denmark, Norway, and Sweden. Patients who had taken medications from either class within the past two years were excluded. Drug treatment, demographics, vital status, and socioeconomic data were obtained from registers, in addition to hospital and outpatient visits and diagnostic codes. To control for confounders, they used propensity scores using logistic regression to control for demographic and socioeconomic variables, comorbidities, drug treatment and health care use. Missing values were accounted for by using a missing value category. The coprimary outcomes were composite cardiovascular events (myocardial infarction, stroke, and cardiovascular death) and heart failure (hospitalization). The secondary outcomes were the individual components of major cardiovascular events and all-cause mortality. Additional supplementary outcomes included lower limb amputation and diabetic ketoacidosis. For statistical analysis, cox proportional hazards regression was used to estimate hazard ratios. Wald test was used to assess for heterogeneity between subgroups in the subgroup analyses. The additional analysis included the As-treated exposure definition. It was the treatment duration based on the estimated number of days covered by filled prescriptions, allowing for up to 90 days between prescriptions (gap period) and after the last prescription to allow for irregular drug use and the capture of events occurring shortly after treatment cessation. The additional analysis included periods of 30 and 60 days. Sensitivity analysis was performed to adjust for HbA1c, blood pressure, estimated glomerular filtration rate, albuminuria, body mass index, and smoking status. Markov Chain Monte Carlo method was used for imputed data for missing values for these categories. Additional sensitivity analyses were conducted regarding each country.

There were 20983 patients in each group. Groups’ characteristics were well balanced with a mean age of 61, a male population of 60%, a history of major cardiovascular disease of 19%, and a history of heart failure of 6%. In the primary intention-to-treat analysis, the mean follow-up for the SGLT-2i group was 1.1 years vs. 1.7 years in the DPP4i group. In the additional as-treated analysis, the mean follow up was 0.7 years in the SGLT2i group and 0.9 years in the DPP4i group. Regarding primary outcomes, the hazard ratio for SGLT-2i vs. DPP4i was 0.94 (95% CI 0.84 to 1.06) for major cardiovascular events and 0.66 (0.53 to 0.81) for heart failure. For secondary outcomes, hazard ratio was 0.99 (95% confidence interval 0.85 to 1.17) for myocardial infarction, 0.94 (0.77 to 1.15) for stroke, 0.84 (0.65 to 1.08) for cardiovascular death, and 0.80 (0.69 to 0.92) for any cause death. In the as-treated analysis, the hazard ratio for the major cardiovascular events composite outcome was 0.84 (0.72 to 0.98), driven by the cardiovascular death component. The hazard ratio for heart failure was 0.55 (0.42 to 0.73). For subgroup analyses, patients with a history of major cardiovascular events or a history of heart failure had significantly different incidence rates vs. patients without. Significant heterogeneity was only found by sex and age. Sensitivity analyses showed no significant differences. Hazard ratios comparing SGLT2 inhibitors with DPP4 inhibitors were only significant for diabetic ketoacidosis 2.14 (1.17 to 4.09).

In conclusion, this study has found that SGLT2i were found to reduce the risk of heart failure and all-cause mortality in comparison to DPP4i. Reduced risk of a cardiovascular event that was driven by cardiovascular death was found in the as-treated analyses. Limitations of the study were the short median follow-up period in the SGLT2 group (1.1 years); the presence of residual confounding because it’s an observational study; most patients observed were on dapagliflozin (other SGLT2i have stronger data regarding CV outcomes). Future studies should host a longer follow-up period to be able to detect a difference in major cardiovascular event outcomes.

Practice Pearls:

  • The use of SGLT2 inhibitors is associated with a reduced risk of heart failure and any cause of death when comparing it to DPP4 inhibitors.
  • The use of SGLT2 inhibitors was not found to be associated with a reduced risk of major cardiovascular events.
  •  When comparing the risk of ketoacidosis between SGLT2 inhibitors vs. DPP4 inhibitors, the risk is higher with SGLT2 inhibitors.

Reference for “SGLT-2i Effects on Major Cardiovascular Events and Heart Failure”:
Pasternak, Björn, et al. “Use of Sodium-Glucose Cotransporter 2 Inhibitors and Risk of Major Cardiovascular Events and Heart Failure: Scandinavian Register Based Cohort Study.” Bmj, 2019, p. l4772.

Nour Salhab, Pharm.D. Candidate, USF College of Pharmacy


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