Introduction
Almost a decade ago the investigators of the EMPA-REG OUTCOME1 trial reported that empagliflozin (sodium-glucose cotransporter-2 [SGLT-2] inhibitor), a glucose-lowering drug, not only reduced the occurrence of the primary cardiovascular end point but also significantly (by 35%) reduced the incidence of heart failure hospitalizations (HFHs) in high-risk type 2 diabetes mellitus (T2DM) population.2 Since then, this effect has been confirmed and repeated in a broad spectrum of patients with and without DM. Moreover, for the last few years, we have been witnessing gradual extension of the indications for SGLT-2 inhibition, as SGLT-2 inhibitors have been shown to be beneficial in a broad spectrum of diseases (T2DM, HF, and chronic kidney disease [CKD]). According to the latest results of the DELIVER3 (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) and EMPEROR-Preserved6 (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction) trials, SGLT-2 inhibitors improve the outcomes in a wide spectrum of HF patients, irrespectively of their left ventricular ejection fraction (LVEF).
The populations that may potentially benefit from the SGLT-2 inhibitors are of key importance from the clinical and public health standpoints for 2 main reasons. Firstly, the calculated relatively low number needed to treat (NNT) with SGLT-2 inhibitors should, at least theoretically, translate into considerable clinical benefit and substantial reduction in cardiovascular deaths and hospitalizations. Secondly, the target populations are patients suffering from civilizational diseases with very high prevalence, such as T2DM, HF, and CKD.
Our study aimed to quantify the estimated benefit (in terms of mortality and prevention of HFHs) from the initiation of SGLT-2 inhibitors in all potential patients with T2DM, CKD, and HF in the Polish population.
Patients and methods
We utilized epidemiologic data from the Polish Ministry of Health for the year 20214 to estimate the number of Polish patients with indications for SGLT-2 inhibitors. We adjusted the population size for inclusion criteria and potential overlap between the studied groups. Furthermore, we analyzed data from several clinical trials, including DAPA-HF5 (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), DELIVER, EMPEROR, DECLARE-TIMI 588 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), DAPA-CKD9 (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease), and EMPA-KIDNEY10 (Empagliflozin Outcome Trial in Patients with Chronic Kidney Disease) to obtain the calculated NNT. Where it was not applicable, we calculated NNT using the GraphPad Prism software (GraphPad Software, San Diego, California, United States). Finally, based on the available data, we assessed the potential number of prevented outcomes for eligible patients in the Polish population. To calculate the CI, we relied on the NNT and 95% CIs provided by the analyzed studies.
Ethics
Our work was based on existing research studies and did not involve direct patient interaction or data collection. As a result, it did not require institutional review board approval or ethics committee oversight. Therefore, obtaining written informed consent from patients was not necessary for our analysis.
Results
Heart failure
There is an estimated number of 741 582 patients with HF in the Polish population. As many as 336 455 of them (45%) are patients suffering from HF with reduced ejection fraction (HFrEF), and 405 126 (55%) from heart failure with preserved ejection fraction (HFpEF).
Type 2 diabetes mellitus
The Polish population comprises approximately 2 324 596 patients suffering from T2DM. The overlap with HF is 22% (511 411 patients). The final number of T2DM patients eligible for SGLT-2 inhibitors is 1 813 115.
Chronic kidney disease
The estimated number of patients with CKD in the Polish population is 238 000, 11% of them (23 100) suffer also from HF, and the number of patients with end-stage CKD is 28 000. The final number of CKD patients eligible for SGLT-2 inhibitors is 186 900.
Total estimated number of patients eligible for sodium-glucose cotransporter-2 inhibitors in Poland
After adjustments for inclusion criteria and potential overlap, the estimated number of patients eligible for SGLT-2 inhibitors in the Polish population is 2 741 667.
The estimated number of outcomes potentially prevented by sodium-glucose cotransporter-2 inhibitors
In Table 1 we present the estimations of potentially prevented outcomes in HF, T2DM, and CKD, if all eligible patients received an SGLT-2 inhibitor, at the population level. In brief, the SGLT-2 inhibitor treatment in all HF patients should translate into 10 906 (95% CI, 2649–19 515) fewer cardiovascular deaths during the median 1.8 years of follow-up (IQR, 1.4–2.5), and by 43 622 (95% CI, 33 708–52 970) lower number of HF hospitalizations. Similarly, the treatment should prevent 12 220 (95% CI, 1935–23 218) cardiovascular deaths in the patients with T2DM.
Outcome | Study name | Median follow-up time, y | NNT (95% CI) | Estimated number of patients meeting the trial criteria in the Polish population | Estimated number of potentially prevented cases (95% CI) |
---|---|---|---|---|---|
HF | |||||
CV death | DAPA-HF + DELIVER5 | 1.8 | 68 (38–280) | 741 582 | 10 906 (2649–19 515) |
ACM | 67 (36–600) | 11 068 (1236–20 600) | |||
Total HF hospitalizations | 17 (14–22) | 43 622 (33 708–52 970) | |||
First HF hospitalization | 32 (22–48) | 23 174 (15 450–33 708) | |||
CV death or HF hospitalization | 26 (19–41) | 28 522 (18 087–39 031) | |||
CV death or HF hospitalization | EMPEROR–preserved6 | 2.2 | 31 (20–71) | 405 126 | 13 069 (5705–20 256) |
HF hospitalization | 32 (22–63) | 12 660 (6431–18 415) | |||
CV death or HF hospitalization | EMPEROR–reduced7 | 1.3 | 19 (13–37) | 336 455 | 17 708 (9093–25 881) |
HF hospitalization | 20 (13–35) | 16 823 (9613–25 881) | |||
T2DM and HFrEF | |||||
CV death | DECLARE-TIMI 588 | 4.2 | 19 (10–120) | 232 181 | 12 220 (1935–23 218) |
ACM | 14 (8–54) | 16 584 (4300–29 023) | |||
CV death or HF hospitalization | 12 (7–49) | 19 348 (4738–33 169) | |||
CKD | |||||
Sustained eGFR, declined ESKD, CV or renal death | DAPA-CKD9 | 2.4 | 19 (15–27) | 186 900 | 12 220 (1935–23 218) |
Progression of kidney disease or CV death | EMPA-KIDNEY10 | 2.0 | 35 (23–73) | 186 900 | 5440 (2560–8126) |
Abbreviations: ACM, all-cause mortality; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; NNT, number needed to treat; T2DM, type 2 diabetes mellitus |
Discussion
Concerning the new recommendations in Poland, there are 2 741 667 patients eligible for SGLT-2 inhibitor therapy. The most accurate data are available for HF. The DELIVER and EMPEROR studies have confirmed the effectiveness of this therapy in this patient population, irrespective of LVEF value, with a significant reduction in key end points.
Broad application of SGLT-2 inhibitors in HF can prevent approximately 11 068 deaths of any cause, 10 906 deaths from cardiovascular causes, and 43 622 HFHs, including 23 174 first-time hospitalizations, within a median period of about 1.8 years (IQR, 1.4–2.5) at the population level. These numbers have significant implications in not only medical but also societal terms, with associated improvements in the patient quality of life, reduced treatment costs, and a decrease in premature deaths in the Polish population.
To our knowledge, this is the first time the analysis has been expanded to include patients with T2DM and CKD, where the use of SGLT-2 inhibitors provides tangible benefits.
Due to the lack of accurate epidemiologic data, our analysis is only an estimation. Therefore, the final numbers of prevented outcomes are based on the patients meeting the inclusion criteria of specific clinical trials. Probably a larger number of patients is eligible for SGLT-2 inhibitor therapy based on the current knowledge. Additionally, epidemiologic data rely on registries of reported patients, which may significantly differ from the actual number of patients with the given condition. Despite the lack of information regarding the coexistence of HF, T2DM, and CKD in Poland, we suspect that our data are underestimated, and the benefits of incorporating SGLT-2 inhibitors in therapy may be even bigger in the Polish population at large.
Limitations
The study is not free from limitations. Our analysis does not provide precise data and is only an estimation. The final number of patients benefiting from the inclusion of SGLT-2 inhibitors may vary. Despite reaching out to the appropriate government bodies, obtaining the exact number of patients with HF, T2DM, and CKD in Poland was not feasible. The ratio of patients with HF and reduced vs preserved LVEF was estimated based on available population studies.
Gracjan Iwanek, MD, Institute of Heart Diseases, Wroclaw Medical University, ul. Borowska 213, 50-566 Wrocław, Poland, phone: +48 71 733 11 12, email: giwanek95@gmail.com
May 15, 2023.
June 26, 2023.
July 4, 2023.
We acknowledge the Wroclaw Medical University for providing a platform to conduct this study and prepare this manuscript.
This research was financially supported by a statutory grant to the Institute of Heart Diseases, Wroclaw Medical University, Poland (SUBZ.A460.23.005).
None declared.
Iwanek G, Zymliński R, Ponikowski P, Biegus J. Estimated population-level benefits of sodium-glucose cotransporter-2 inhibitors introduction in the Polish population. Pol Arch Intern Med. 2023; 133: 16524. doi:10.20452/pamw.16524
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