Cardiovascular Benefits of SGLT-2 Inhibitors

In addition to clinical trials, does data from a meta-analysis of retrospective cohort studies support the benefits of SGLT-2 inhibitors?

The ADA guideline for managing type 2 diabetes recommends sodium-glucose co-transporter-2 (SGLT-2) inhibitor as a second-line pharmacological option for patients at risk or who have established cardiovascular disease. The evidence came from individual trials showing that SGLT-2 inhibitors reduced cardiovascular outcomes (major adverse cardiovascular event [MACE], non-fatal myocardial infarction, heart failure) and non-fatal stroke. However, the class effect of SGLT-2 inhibitors is unknown since the data came from individual trials for each SGLT-2 inhibitor agent. Additionally, the effects on the outcomes differed among trials. For example, the EMPAREG and SCORED trials showed the benefit of reducing the risk for non-fatal myocardial infarction for empagliflozin and sotagliflozin, respectively. However, the same benefit was not seen in the VERTIS CV trial for ertugliflozin. Multiple retrospective cohort studies have been conducted to investigate the effects of SGLT-2 inhibitors from the daily clinical practice data. Therefore, Mascolo A. et al. conducted a meta-analysis review of these studies to evaluate the benefits of SGLT-2 inhibitors on stroke outcomes, cardiovascular outcomes, and mortality outcomes.

This analysis reviewed all retrospective cohort studies published between 2012 and 2020 to include 20 studies that meet the following criteria: containing outcomes of non-fatal stroke, or cardiovascular or mortality; comparators of dipeptidyl peptidase-4 (DPP-4) inhibitors or non-SGLT-2 inhibitors; subjects with type 2 diabetes; and utilizing Cox regression model for analysis. All studies have good quality according to the Newcastle-Ottawa Scale. The primary endpoint was to evaluate the risk of SGLT-2 inhibitors regarding outcomes of non-fatal stroke, cardiovascular outcomes, cardiovascular death, or overall death compared to DPP-4 inhibitors. The secondary outcome was the same assessment but to compare SGLT-2 inhibitors with non-SGLT-2 inhibitors. DPP-4 inhibitors were used in the primary assessment because it is a standard second-line agent for managing type 2 diabetes, and it has no benefits on cardiovascular outcomes.

In the comparison between SGLT-2 inhibitors versus DPP-4 inhibitors, the SGLT-2 inhibitors showed benefit for reduced incidence of stroke (HR 0.89, 95% CI 0.82 to 0.96, moderate heterogeneity), hospitalization for heart failure (HR 0.69, 95% CI 0.63 to 0.76, moderate heterogeneity), and MACE outcomes (HR 0.86, 95% CI 0.78 to 0.95, moderate heterogeneity). However, SGLT-2 inhibitors showed no benefit in reducing the risk for non-fatal myocardial infarction (HR 0.93, 95% 0.86 to 1.00, consistent heterogeneity). In the mortality outcomes, SGLT-2 showed significant benefit in reducing the hazard for cardiovascular death (HR 0.82, 95% CI 0.67 to 0.99, consistent heterogeneity) and overall death (HR 0.74, 95% CI 0.64 to 0.86, high heterogeneity).

In the comparison between SGLT-2 inhibitors versus non-SGLT-2 inhibitors, SGLT-2 inhibitors were associated with a significant reduction in the risk for stroke (HR 0.82, 95% CI 0.77 to 0.91, low heterogeneity), non-fatal myocardial infarction (HR 0.84, 95% CI 0.79 to 0.90, consistent heterogeneity), hospitalization for heart failure (HR 0.70, 95% CI 0.64 to 0.78, moderate heterogeneity), and MACE outcomes (HR 0.81, 95% CI 0.75 to 0.88, low heterogeneity). Additionally, SGLT-2 inhibitors have a significant lower risk in cardiovascular death (HR 0.57, 95% CI 0.42 to 0.76, moderate heterogeneity) and overall death (HR 0.58, 95% CI 0.54 to 0.62) compared to non-SGLT-2 inhibitors.

Data from this analysis supports the findings from pre-existing studies regarding the cardiovascular protective effect of SGLT-2 inhibitors in patients with type 2 diabetes. However, one of the limitations is that the nature of this study hindered further analysis between SGLT-2 inhibitors. For example, the SCORED trials showed a 34% risk reduction in the combined fatal and non-fatal stroke outcome with sotagliflozin. On the other hand, the CANVAS program showed no benefit in reducing the incidence of stroke with canagliflozin. Therefore, robust evidence from one agent can affect the overall conclusion in meta-analysis. In conclusion, SGLT-2 inhibitors provide benefits in cardiovascular outcomes and cardiovascular death. However, familiarity with each SGLT-2 inhibitor is essential in providing individualized therapy for each patient.

Practice Pearls:

• An SGLT-2 inhibitor is a second-line option for patients with type 2 diabetes at risk or who have established cardiovascular disease.
• SGLT-2 inhibitor provides benefit in reducing the risk of cardiovascular outcomes for patients with type 2 diabetes.
• This study has significant heterogeneity across all studies, in which the effect for each SGLT-2 inhibitor agent needed to be reviewed individually from their perspective study.

References for “Cardiovascular Benefits of SGLT-2 Inhibitors”:
Mascolo, Annamaria et al. “SGLT-2 inhibitors reduce the risk of cerebrovascular/cardiovascular outcomes and mortality: A systematic review and meta-analysis of retrospective cohort studies.” Pharmacological research vol. 172 (2021): 105836.

American Diabetes Association. “9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2021.” Diabetes care vol. 44, Suppl 1 (2021): S111-S124.

Cannon, Christopher P et al. “Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes.” The New England journal of medicine vol. 383,15 (2020): 1425-1435.

Zinman, Bernard et al. “Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes.” The New England journal of medicine vol. 373,22 (2015): 2117-28.

Bhatt, Deepak L et al. “Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease.” The New England journal of medicine vol. 384,2 (2021): 129-139.

Ding Nguyen, PharmD Candidate, University of South Florida Taneja College of Pharmacy