Combination of SGLT2i and nonsteroidal MRA improves estimated event-free survival in T2D and CKD
Estimated lifetime benefit of novel pharmacological therapies in patients with type 2 diabetes and chronic kidney disease: A joint analysis of randomized controlled clinical trials
Literature - Heerspink HJL, Vart P, Jongs N, et al. - Diabetes Obes Metab. 2023 Nov;25(11):3327-3336. doi: 10.1111/dom.15232Introduction and methods
Background
SGLT2 inhibitors and the selective, nonsteroidal MRA finerenone have been shown to improve CV and renal outcomes in patients with both T2D and CKD [1-3]. In addition, a recent RCT showed an additive effect on albuminuria and blood pressure with combination treatment with an SGLT2 inhibitor and MRA in CKD patients with and without T2D compared with either drug alone [4]. Still, the implementation of these therapies in routine practice is low.
Aim of the study
The authors estimated the lifetime benefit of SGLT2 inhibitor and nonsteroidal MRA combination treatment versus conventional therapy in patients with T2D and CKD.
Methods
The authors used overall trial-level estimates from 2 pivotal placebo-controlled phase 3 RCTs in which the efficacy and safety of canagliflozin (CREDENCE trial; n=4401) or finerenone (FIDELIO-CKD trial, n=5674) were assessed [1,3]. To estimate long-term gains in event-free and overall survival, data of T2D patients in the placebo group of the DAPA-CKD trial (n=1451) were used [2]. All participants in these trials were prescribed an ACEi or ARB.
To derive combined treatment effects and project substantial gains in event-free survival, previously validated methods from cardiology trials were applied. To assess the robustness of the results in a nonclinical setting, data from the observational CRIC (Chronic Renal Insufficiency Cohort) Study were used [5].
Outcomes
The primary endpoint was a composite outcome of sustained doubling of serum creatinine, end-stage kidney disease (ESKD; defined as sustained eGFR ≤15 mL/min per 1.73 m², initiation of dialysis for ≥30 days, or kidney transplantation), or death because of kidney failure. The secondary endpoint was ESKD. Additional endpoints were HF hospitalization and all-cause mortality.
Main results
- The HR for the estimated relative treatment effect of the canagliflozin/finerenone combination therapy as an adjunct to conventional treatment (ACEi or ARB) versus conventional treatment only on the primary composite endpoint was 0.50 (95%CI: 0.44–0.57). The absolute risk reduction over 3 years was 7.7%–10.1% (number needed to treat: 10–13).
- For the secondary endpoint (ESKD), the HR for the derived treatment effect of the combination treatment versus conventional treatment was 0.59 (95%CI: 0.51–0.69), whereas it was 0.52 (95%CI: 0.44–0.63) for HF hospitalization and 0.75 (95%CI: 0.65–0.86) for all-cause mortality.
- For patients starting treatment at 50 years of age, the estimated survival free of the primary endpoint was 16.7 years (95%CI: 15.5–17.9) with combination treatment versus 10.0 years (95%CI: 6.8–12.3) with conventional treatment (difference: 6.7 years; 95%CI: 5.5–7.9). In comparison, a 60-year old patient receiving the combination treatment was estimated to gain 3.2 additional years (95%CI: 2.7–3.7) free of the primary endpoint compared with conventional treatment.
- At age 50 years, the estimated event-free survival of ESKD was 19.3 years (95%CI: 17.9–20.4) with combination treatment versus 14.4 years (95%CI: 10.5–17.1) with conventional treatment (difference: 4.8 years; 95%CI: 3.5–6.0), whereas the estimated overall survival was 22.1 years (95%CI: 21.2–23.0) and 20.1 years (95%CI: 15.9–21.3), respectively (difference: 2.0 years; 95%CI: 1.1–2.9).
- Repeated analysis using the observational study data showed an estimated gain in event-free survival of the primary endpoint of 6.3 years (95%CI: 5.2–7.3) for patients starting treatment at age 50 years.
- Finally, a sensitivity analysis was performed that assumed lower treatment adherence (70% of observed adherence) and less pronounced efficacy (70% of observed efficacy with 2% yearly decline) of combination treatment in the real world compared with those observed in the RCTs. In this conservative scenario, the estimated gain in event-free survival of the primary endpoint for patients starting treatment at age 50 years was 2.5 years (95%CI: 2.0–2.9).
Conclusion
This study estimated the lifetime benefit of SGLT2 inhibitor and nonsteroidal MRA combination treatment versus conventional therapy. Analysis of pivotal RCT data showed that combination treatment with canagliflozin and finerenone reduced the risk of adverse renal outcomes by 50% in patients with T2D and CKD compared with conventional treatment (ACEi or ARB) only. For those starting combination treatment at age 50 years, the estimated gain in survival free of this primary composite outcome was ~7 years, whereas the estimated gain in overall survival was 2 years. A real-world scenario assumed an estimated gain in event-free survival of the primary endpoint of 2.5 years.
The authors believe their findings could aid patients and their physicians. “Because the progression of diabetic kidney disease takes many years and trials are conducted over a follow-up shorter than life expectancy of patients, projections of lifetime application beyond the duration of a trial may help in communicating potential lifetime benefits and implementation of new therapies.”
References
1. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295-2306.
2. Heerspink HJL, Stefansson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383:1436-1446.
3. Bakris GL, Agarwal R, Anker SD, et al. Effect of Finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020;383:2219-2229.
4. Provenzano M, Puchades MJ, Garofalo C, et al. Albuminuria-lowering effect of dapagliflozin, eplerenone, and their combination in patients with chronic kidney disease: a randomized crossover clinical trial. J Am Soc Nephrol. 2022;19:ASN.2022020207:1569-1580.
5. Feldman HI, Appel LJ, Chertow GM, et al. Chronic renal insufficiency cohort (CRIC) study investigators. The chronic renal insufficiency cohort (CRIC) study: design and methods. J Am Soc Nephrol. 2003;14:S148-S153.
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