Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

• Perkovic V, Jardine MJ, Neal, B, et al. N Engl J Med. 2019;380(24):2295–2306.

An overview of key findings from the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation Trial) trial¹

Type 2 diabetes mellitus (T2DM) is considered a leading cause of chronic kidney disease (CKD) and CKD-related deaths^2,3. At the time of the CREDENCE study, only renin-angiotensin system blockade was approved for renoprotection in patients with T2DM^1,4,5. Considering the ongoing increase in prevalence of T2DM⁶, there was a need for long-term, effective treatments which provide renoprotection in this population.

Although sodium–glucose cotransporter 2 (SGLT2) inhibitors were originally developed to lower blood glucose in patients with T2DM, a reduction in cardiovascular (CV) events was observed with SGLT2 inhibitors in clinical trials^7–9, and associated secondary/exploratory analyses have suggested potential benefits for renal outcomes^9–11. However, these findings were limited by the low risk of kidney failure in the trial populations, and few reached end-stage kidney disease (ESKD)^9–11.

To better characterise the impact of SGLT2 inhibitors on renal function, the CREDENCE trial was designed to assess the effects of canagliflozin on renal outcomes in patients with T2DM and albuminuric chronic kidney disease (CKD)¹

Based on the results of this trial:

• Canagliflozin was the first SGLT2 inhibitor to be FDA-approved for prevention of kidney failure in patients with T2DM¹²
• The indication for canagliflozin was extended in Europe to include treatment of diabetic kidney disease in patients with T2DM¹³

What did the CREDENCE investigators do?

CREDENCE was a randomised, double-blind, placebo-controlled Phase 3 clinical trial conducted across 690 sites in 34 countries¹.

Adults aged ≥30 years, with T2DM (HbA_1c level of 6.5–12.0% [or 6.5–10.5% in Germany]), CKD (defined as an estimated glomerular filtration rate [eGFR] of 30–<90 mL/minute/1.73m²) and albuminuria (urinary albumin-to-creatinine ratio, >300–5000) were recruited into the study. Approximately 60% of participants were to have an eGFR of 30–<60 mL/min/1.73m²). Participants were on a stable dose of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for at least 4 weeks prior to randomisation¹.

Following screening, 4,401 participants were randomly assigned to canagliflozin (n = 2,202; 100 mg orally, once daily) or placebo (n = 2,199)¹.

Trial visits were conducted at 3, 13 and 26 weeks after randomisation, and participants subsequently alternated between telephone calls and in-clinic visits at 13-week intervals¹.

The primary outcome was a composite of ESKD (dialysis for ≥30 days, kidney transplantation, or an eGFR of <15 ml/min/1.73 m² sustained for ≥30 days), doubling of serum creatinine level from baseline (sustained for ≥30 days), or death from renal or CV disease¹. Secondary outcomes were tested sequentially in hierarchical order.

What did the CREDENCE investigators find?

Primary and secondary efficacy outcomes

After the planned interim analysis, the CREDENCE trial was stopped early as pre-specified stopping criteria for efficacy had been met¹. After a median follow-up of 2.62 years, a significant reduction was observed in the event rate for the primary composite outcome of ESKD, doubling of serum creatinine level, or renal or CV death, in the canagliflozin group compared to placebo (43.2 and 61.2 per 1000 patient-years, respectively) (Figure 1)¹.

Figure 1. Results for (A) the primary composite outcome (ESKD, doubling of serum creatinine, renal or CV death), and (B) the renal-specific composite outcome (ESKD, doubling of serum creatinine, or renal death) from the CREDENCE trial (Adapted¹). CI, confidence interval; HR, hazard ratio.

This translated to a 30% lower relative risk in the canagliflozin group for the primary composite efficacy outcome (ESKD, doubling of serum creatinine, renal or CV death), compared to placebo (HR, 0.70; 95% CI, 0.59–0.82; P=0.00001)¹

A statistically significant reduction was observed across the renal components of the composite outcome, except for renal death¹.

For secondary outcomes, there was a significantly lower risk of the following in the canagliflozin group compared to placebo¹:

• Composite outcome of CV death or hospitalisation for HF (hazard ratio [HR] 0.69; 95% confidence interval [CI], 0.57–0.83; P<0.001)
• Composite outcome of CV death, MI, or stroke (HR 0.80; 95% CI, 0.67–0.95; P=0.01)
• Hospitalisation for HF (HR 0.61; 95% CI, 0.47–0.80; P<0.001)

A 34% lower risk was observed in the canagliflozin group for the composite secondary outcome of ESKD, doubling of the serum creatinine level, or renal death, compared to placebo (HR 0.66; 95% CI, 0.53–0.81; P<0.001⁾¹

However, as there was no significant difference between groups for risk of CV death (HR 0.78; 95% CI, 0.61–1.00; P=0.05), no formal testing was performed on differences in all subsequent secondary outcomes in the hierarchical testing sequence¹.

Safety outcomes

Similar rates of AEs and serious AEs were observed across the canagliflozin and placebo groups (HR 0.87; 95% CI, 0.82–0.93 and HR 0.87; 95% CI, 0.79–0.97, respectively), although there was a higher relative risk of serious AEs related to study drug observed in the canagliflozin group compared to placebo (HR 1.45; 95% CI, 0.98–2.14)¹.

A higher incidence of diabetic ketoacidosis was observed in the canagliflozin group compared to placebo (2.2 vs. 0.2 per 1000 patient-years)¹.

Why was the CREDENCE trial stopped early?

After the planned interim analysis, the trial was stopped early on recommendation from the independent data and safety monitoring committee (DSMC), as the prespecified efficacy criteria for early cessation had been achieved. Prespecified stopping criteria included clear evidence of benefit for the primary outcome (P<0.01), and the composite of ESKD or death from renal or CV causes (P<0.025), considering the overall balance of risks and benefits¹.

In summary, the findings of the CREDENCE study indicated canagliflozin was effective in reducing the risk of adverse cardiac and renal outcomes in patients with T2DM and CKD at high risk for kidney failure, when used on a background of renin-angiotensin blockade¹

References

1. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. New England Journal of Medicine. 2019;380(24):2295–2306.
2. Deng Y, Li N, Wu Y, Wang M, Yang S, Zheng Y, et al. Global, regional, and national burden of diabetes-related chronic kidney disease from 1990 to 2019. Frontiers in Endocrinology. 2021;12. doi:10.3389/fendo.2021.672350.
3. Hussain S, Chand Jamali M, Habib A, Hussain MS, Akhtar M, Najmi AK. Diabetic kidney disease: An overview of prevalence, risk factors, and biomarkers. Clinical Epidemiology and Global Health. 2021;9:2–6.
4. Brenner B, Cooper M, de Zeeuw D, Keane W, Mitche W, Parving H, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. New England Journal and Medicine. 2001;345(12):861–869.
5. Lewis E, Hunsicker L, Clarke W, Berl T, Pohl M, Ritz E, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. New England Journal of Medicine. 2001;345(12): 851–860.
6. Khan MAB, Hashim MJ, King JK, Govender RD, Mustafa H, Kaabi J al. Epidemiology of type 2 diabetes - Global burden of disease and forecasted trends. Journal of Epidemiology and Global Health. 2020;10(1):107–111.
7. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. New England Journal of Medicine. 2017;377(7):644–657.
8. Zinman B, Wanner C, Lachin J, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. New England Journal of Medicine. 2015;373:2117–2128.
9. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. New England Journal of Medicine. 2019;380(4):347–357.
10. Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, Erondu N, Shaw W, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. The Lancet Diabetes and Endocrinology. 2018;6(9):691–704.
11. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. New England Journal of Medicine. 2016;375(4):323–334.
12. Janssen Pharmaceuticals. Canagliflozin (Invokana®) prescribing information (US). 2013;Updated August 2020. https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/INVOKANA-pi.pdf. Accessed 24 January 2022.
13. Janssen-Cilag International NV. Canagliflozin (Invokana) EPAR product information. 2013;Updated Nov 2021. https://www.ema.europa.eu/en/medicines/human/EPAR/invokana#product-information-section. Accessed 24 January 2022.