Cost-effectiveness of Empagliflozin

Examining both the clinical outcomes and cost-effectiveness of empagliflozin for patients with type 2 diabetes with established cardiovascular disease.

Using antidiabetic medications has the goal of preventing microvascular and macrovascular complications, increasing life expectancy, and improving the quality of life. One aspect that is important when determining medication regimens for patients with diabetes is the cost-effectiveness of the medication. Since diabetes is associated with increased costs due to related complications, it is important to consider these options. This study developed an economic model based on the EMPA-REG OUTCOME trial to assess clinical and cost outcomes in patients with type 2 diabetes with established cardiovascular disease.

Patients from the EMPA-REG OUTCOME trial were randomized to either take empagliflozin or placebo along with other antidiabetics, antihyperlipidemic, antihypertensive, and anticoagulants. The developed model observed the predicted time to events based on clinical prognostic factors leading to the events. The follow-up (observed) time was about three years long. Following the event, the participants would either exit the model if a fatal event had occurred or time horizon had ended or would remain in the model, and their data would be updated. Data for patients were selected randomly from the trial. The overall trial population was used to evaluate the effect of treatment on costs and quality of life. Ten clinical events were tracked: cardiovascular death, non-fatal MI, non-fatal stroke, unstable angina hospitalization, heart failure hospitalization, transient ischemic attack, revascularization, new onset of macroalbuminuria, renal injury (doubling of serum creatinine, with eGFR <45 ml/min/1.73 m2), and renal failure (initiation of continuous renal replacement therapy).  The hazards of each event were extrapolated by parametric models to predict the simulation over a lifetime. For modeled events, they fit a population-level event free-survival function using parametric distribution; then, they used cox regression analysis to generate individual-level risk from participant’s characteristics and event history. An event-free survival curve was populated for population-level data while parametric survival models were populated for individual-level data. The multivariate parametric equation, which was used for candidate predictors, was then trended to reach a univariate analysis with P<0.02 considered significant. Subgroup analysis was also performed; P ≤0.05 was considered significant.

Additionally, renal events were computed as predictors of risk of future cardiovascular events and mortality, but not vice-versa. The models generated captured costs associated with empagliflozin use and the acute management of each event. Long-term management costs were not included (inpatient costs, not long-term outpatient costs). To measure the length of life adjusted for quality of life, health outcomes were expressed in quality-adjusted life-years (QALYs). Each event accumulated was summed and adjusted. Univariate analysis was also performed.

As a result of following 10,000 participants for about three years, validation results were sensitive to random variation. The largest deviations were in the rates of revascularization (model HR 0.92) and cardiovascular death (model HR 0.70), both of which show rate ratios that are slightly less favorable to empagliflozin (HR 0.86) than the trial data (HR 0.62).  Patients who had received empagliflozin vs. standard of care had shown an improvement in survival on an average of 2 years longer. This resulted from the occurrence of 7 events/100 patient-years with empagliflozin vs. 8.6 events/100 patient-years in the standard of care group. Modeled participants who received empagliflozin and standard of care were estimated to have a higher rate of non-cardiovascular-related mortality but had a lower rate of death from any cause. Longer overall survival and reduced rates of clinical events translated into 1.0 QALY. Event costs were reduced by 1177 UK pounds/ participant (1449.36 USD). This resulted in an incremental cost-effectiveness ratio (ICER) of 4083 UK pounds/ QALY (5027.81 USD), below the accepted 30,000 UK pound/QALY (36,942 USD) cost-effectiveness threshold. For one-way sensitivity analyses, all ICERs yielded below the 30,000 UK pound/QALY cost-effectiveness threshold. Empagliflozin’s effect on mortality had an ICER of 5978 UK pounds/ QALY (7361.31 USD). Using the utility parameter with no event history yielded 3378-5160 UK pounds/QALY (4159.67 – 6354.02 USD). Empagliflozin showed consistent cost-effectiveness across all analyses with no dominance over a specific endpoint.

In conclusion, empagliflozin use in patients with type 2 diabetes, who also have a high cardiovascular risk, was found to be highly cost-effective for treatment. It was found to reduce cardiovascular mortality and cardiovascular events along with their costs. Limitations of this study include the limited generalizability of the study because they used the population from the EMPA-REG OUTCOME study, the inability of the model to capture evolving treatment sequencing or diabetes-related complications (blindness, amputations, and diabetic ketoacidosis), and the sensitivity of the model to the impact of subsequent events on future event.

Practice Pearls:

• The use of empagliflozin (in addition to standard care) in patients with type 2 diabetes and established cardiovascular disease is associated with decreased costs due to decreased risk of cardiovascular events.
• Empagliflozin’s use can benefit both patients and payers due to its association with decreased costs. 

Reference for “Cost-effectiveness of Empagliflozin”:
Kansal, A., et al. “Cost‐Effectiveness Analysis of Empagliflozin Treatment in People with Type 2 Diabetes and Established Cardiovascular Disease in the EMPA ‐ REG OUTCOME Trial.” Diabetic Medicine, 2019

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

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