How many patients must be treated with Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors to prevent one cardiovascular death?

From the Guidelines

To prevent one cardiovascular death, approximately 27 patients with established cardiovascular disease must be treated with SGLT2 inhibitors, such as empagliflozin, for about 3 years. This estimate is based on the EMPA-REG OUTCOME trial, which demonstrated a 38% reduction in cardiovascular death with empagliflozin treatment compared to placebo 1. The number needed to treat (NNT) can be calculated from the absolute risk reduction, which was 2.2% (5.9% - 3.7%) over a median follow-up of 3.1 years.

Key points to consider when prescribing SGLT2 inhibitors include:

• The patient population: those with established cardiovascular disease or heart failure tend to have a lower NNT (around 20-25) compared to those without established cardiovascular disease (around 30-40)
• The specific SGLT2 inhibitor used: empagliflozin, dapagliflozin, and canagliflozin have all shown mortality benefits in clinical trials 1
• The duration of treatment: benefits are typically seen after 2-3 years of treatment
• Potential side effects: patients should be monitored for genital mycotic infections, volume depletion, and rare but serious diabetic ketoacidosis

The mechanisms by which SGLT2 inhibitors exert their cardiovascular and renal benefits are not fully understood, but are thought to involve reduced cardiac preload, improved ventricular loading conditions, and direct effects on myocardial metabolism, in addition to increased glucose excretion through the kidneys 1. Overall, the use of SGLT2 inhibitors in patients with established cardiovascular disease or heart failure can be a highly effective strategy for reducing cardiovascular mortality.

From the FDA Drug Label

The treatment effect was due to a significant reduction in the risk of cardiovascular death in subjects randomized to empagliflozin (HR: 0.62; 95% CI 0.49,0. 77), with no change in the risk of non-fatal myocardial infarction or non-fatal stroke Cardiovascular deathc 137 (5.9%) 172 (3.7%) 0.62 (0.49,0.77)

To calculate the number of patients needed to be treated to prevent one cardiovascular death, we can use the number needed to treat (NNT) formula.

• The absolute risk reduction (ARR) can be calculated as follows:
  • ARR = (Risk in the control group) - (Risk in the treatment group)
  • ARR = (137/2333) - (172/4687)
  • ARR = 0.0587 - 0.0367
  • ARR = 0.022
• The NNT is the reciprocal of the ARR:
  • NNT = 1 / ARR
  • NNT = 1 / 0.022
  • NNT ≈ 45.5 Therefore, approximately 46 patients must be treated with Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors to prevent one cardiovascular death 2.

From the Research

Number of Patients Needed to be Treated with SGLT2 Inhibitors

To determine the number of patients that must be treated with Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors to prevent one cardiovascular death, we can look at the following evidence:

• A study published in 2021 3 found that SGLT2 inhibitors significantly reduce all-cause and cardiovascular mortality compared with placebo in patients with heart failure.
• Another study published in 2020 4 reported that the pooled relative risk for death from cardiovascular causes alone was 0.89 (0.81-0.99) in the general population, with a number needed to treat (NNT) of 143 for all-cause mortality.
• A 2022 systematic review and meta-analysis 5 estimated that for 1000 individuals treated over 3.5 years, SGLT2i are expected to decrease the number of deaths from 70 to 61.

Key Findings

Some key findings related to the number of patients needed to be treated with SGLT2 inhibitors to prevent one cardiovascular death include:

• A number needed to treat (NNT) of 143 for all-cause mortality 4
• A NNT of 91 for heart failure hospitalizations 4
• An expected decrease in the number of deaths from 70 to 61 for 1000 individuals treated over 3.5 years 5
• A hazard ratio of 0.86 (0.78-0.96) for cardiovascular mortality, corresponding to a NNT of 23 (18-33) over 3 years 6

Subgroup Analyses

Subgroup analyses have been performed to examine the efficacy of SGLT2 inhibitors in different patient populations, including:

• Patients with heart failure 7, 3
• Patients with type 2 diabetes and albuminuria 6
• Patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 4 These analyses have generally shown that SGLT2 inhibitors are effective in reducing cardiovascular and renal outcomes across different patient subgroups.