Combination Therapy Yields Long-Term Health Outcomes in Patients With Diabetes

SGLT-2 inhibitors and MRA is an efficacious adjunct to conventional treatments for type 2 diabetes and chronic kidney disease.

Compared with conventional treatment, combined therapy of sodium-glucose co-transporter 2 (SGLT-2) inhibitors and mineralocorticoid-receptor antagonists (MRA) yields significant long-term health outcomes in patients with type 2 diabetes and chronic kidney disease (CKD), according to study findings published in Diabetes, Obesity and Metabolism.

Despite findings that demonstrate treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) reduces the risk for heart and kidney failure in patients with type 2 diabetes and CKD, these risks remain high. Compared with these traditional treatments, SGLT2 inhibitors and MRA have demonstrated superior cardiovascular and kidney outcomes. However, real world implementation has been slower than anticipated.

To estimate the lifetime benefit of combination treatment of SGLT-2 inhibitors (canagliflozin) and MRA (finerenone) in patients with type 2 diabetes and CKD, researchers derived data from the placebo-controlled randomized clinical trials CREDENCE ( Identifier: NCT02065791) and FIDELIO-DKD ( Identifier: NCT02540993), respectively.

In these respective trials, the researchers assessed the safety and efficacy of canagliflozin and finerenone compared with placebo and in addition to conventional treatment of ACE inhibitors and ARBs.  

Combined disease-modifying pharmacological treatment with SGLT2 inhibitors, MRAs and endothelin receptor antagonists…prolong overall survival in patients with type 2 diabetes and CKD.

The primary endpoint of the study was a composite of a sustained doubling of serum creatinine, end-stage kidney disease (defined as a sustained estimated glomerular filtration rate of less than or equal to 15 mL/min/1.73 m2, initiation of dialysis for at least 30 days, or kidney transplantation), or death from kidney failure. The secondary outcome was end-stage kidney disease, with heart failure hospitalization and all-cause mortality also examined as endpoints.

The mean ages of patients in the CREDENCE (N=4401) and FIDELIO-DKD (N=5674) trials were 63.0 and 65.6 years, respectively, whereas the mean estimated glomerular filtration rates were 56.2 and 44.3 mL/min/1.73 m2, respectively. All patients were prescribed an ACE inhibitor or ARB.

Compared with conventional treatment alone, an SGLT-2 inhibitor and MRA as an adjunct to conventional treatment yielded a combined treatment effect on:

  • Primary composite kidney function (hazard ratio [HR], 0.50; 95% CI, 0.44-0.57);
  • End-stage kidney disease (HR, 0.59; 95% CI, 0.51-0.69);
  • Hospitalization for heart failure (HR, 0.52; 95% CI, 0.44-0.63); and,
  • All-cause mortality (HR, 0.75; 95% CI, 0.65-0.86).

For patients who initiated treatment at 50 years of age, the estimated event-free survival gains of combined therapy and conventional treatment were 16.7 years (95% CI, 15.5-17.9) and 10.0 years (95% CI, 6.8-12.3), respectively, culminating in a gain of 6.7 years (95% CI, 5.5-7.9).

The overall survival gains of combined and conventional treatments were 22.1 years (95% CI, 21.2-23.0 and 20.1 years (95% CI, 15.9-21.3), respectively, with a difference of 2.0 years (95% CI, 1.1-2.9).

The researchers also found a greater event-free gain among younger patients compared with older patients, as a patient aged 60 years gained an additional 3.2 years (95% CI, 2.7-3.7), whereas a patient aged 70 years gained an additional 1.1 years (95% CI, 0.9-1.2).

Study limitations include the early discontinuation of the CREDENCE trial, which resulted in a potential overestimate of the combined pharmacological treatments’ incremental survival gain, and the lack of data on long-term efficacy. 

According to the researchers, “Combined disease-modifying pharmacological treatment with SGLT2 inhibitors, MRAs and endothelin receptor antagonists, compared with conventional treatment, may substantially improve long-term health outcomes, including kidney failure and heart failure hospitalization, and prolong overall survival in patients with type 2 diabetes and CKD.”

Disclosure: Multiple study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

This article originally appeared on Endocrinology Advisor


Heerspink HJL, Vart P, Jongs N, et al. 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. Diabetes Obes Metab. Published online August 14, 2023. doi:10.1111/dom.15232