Canagliflozin Demonstrates Significant Efficacy in Chronic Kidney Disease: CREDENCE Trial Results Published in NEJM

On the 15th, NEJM published the results of a Phase III clinical trial of Johnson & Johnson’s SGLT2 inhibitor canagliflozin in chronic kidney disease (CKD). This trial, called CREDENCEClinical TrialsRecruitment of 4,400 patients with CKD (GFR 30–90 mL/min/1.73 m² body surface area)DiabetesAmong patients receiving background renin-angiotensin system inhibitors, canagliflozin and placebo were administered, respectively. Over a mean follow-up period of 2.62 years, canagliflozin reduced the primary composite endpoint—comprising end-stage kidney disease (ESKD), deterioration of renal function, and renal or cardiovascular death—by 30% compared with placebo, thereby meeting the trial’s primary endpoint. The risk of ESKD was reduced by 32%. Benefits in secondary endpoints included a 20% reduction in the risk of cardiovascular death or hospitalization and a 39% reduction in the risk of hospitalization for heart failure. The risk of amputation was similar between the two groups.

Drug Source Analysis

Chronic kidney disease (CKD) represents a market potentially larger than that of non-alcoholic steatohepatitis (NASH), with an estimated 10% of the population affected by CKD to varying degrees. Globally, 5–10 million patients die annually from kidney failure, and in the United States alone, 500,000 patients require renal dialysis. However, the kidneys have historically received less attention from the pharmaceutical industry compared to other vital organs such as the liver, brain, and heart. Currently, there are no drugs specifically approved for CKD; management primarily relies on glucose-lowering and antihypertensive agents. In this trial, the reduction in HbA1c was modest, at only 0.25%, suggesting that the observed benefits are unlikely to stem from glycemic control. Although the canagliflozin group showed lower blood pressure and body weight compared to the control group, these differences were not statistically significant. Kidney disease is closely linked to cardiac and skeletal health, and emerging evidence suggests that renal function is also coupled with gastrointestinal and pulmonary functions. Strictly speaking, the human body is an integrated system in which all organs are interconnected. Indeed, current hypotheses propose that the renal benefits of SGLT2 inhibitors may arise from improvements in energy metabolism and inflammatory responses. There is also evidence indicating that enhancements in the renal microenvironment, such as reduced intraglomerular pressure, may contribute to their therapeutic efficacy.

SGLT2 is arguably one of the most understated targets, akin to the "Sweeping Monk" among therapeutic targets. SGLT inhibitors were initially developed asDiabetesDrug Development: Later, three SGLT2 inhibitors demonstrated in large-scale cardiovascular safety trials that they could reduce cardiovascular (CV) risk, primarily the risk of heart failure, suggesting this is likely a class effect. At least empagliflozin has already initiated Phase III clinical trials for heart failure—a rare broad indication for a new drug—and if successful, it may be marketed as a novel class of heart failure medication. Today’s trial indicates that SGLT2 inhibitors may have a place in the treatment of chronic kidney disease (CKD); treating 22 patients for 2.5 years prevents one primary endpoint event, representing a highly significant therapeutic effect. Although the exact mechanism underlying the potent efficacy of SGLT2 inhibitors remains unclear, this once-underestimated glucose-lowering mechanism appears, much like obesity, to potentially serve as a master switch for chronic diseases.

Clinical observation was once a crucial pathway in early drug discovery, but it is no longer the mainstream approach. Although discoveries such as those of ketamine and fenfluramine do occur occasionally, unexpected therapeutic benefits like those of SGLT2 inhibitors in major indications such as heart failure and chronic kidney disease (CKD) are rare. This may represent one of the most significant clinical findings of the past two decades. This progress is partly attributable to Steve Nissen’s 2007 meta-analysis on the cardiovascular risks of rosiglitazone, which directly led toFDAYesDiabetes、Weight LossNew regulatory requirements for cardiovascular safety in pharmaceuticals. It was this requirement that uncovered the cardiovascular benefits of SGLT2 inhibitors; subgroup analyses further demonstrated renal benefits, which subsequently led to the CREDENCE trial in patients with higher-risk chronic kidney disease (CKD). This trial screened over 10,000 patients and spanned five years. Without clinical signals of safety from prior trials, few would have dared to undertake such a costly large-scale study based solely on mechanistic rationale. This situation also reflects that new drug discovery remains an endeavor heavily dependent on fortuitous findings. If someone asks you in the future how to identify a novel-mechanism CKD drug, you might respond with deliberate profundity: “I’m afraid you must first bring to market a class of drugs associated with cardiovascular risk.”DiabetesDrugs (i.e., PPAR agonists).

Although drugs discovered through serendipitous clinical findings are now uncommon, current technologies have advanced significantly compared to the past, enabling more effective elucidation of mechanisms of action. Chemical biology andGenomicsThis approach enables the rapid identification of which target or pathway is responsible for therapeutic efficacy. Other regulatory nodes within this pathway may serve as novel targets for major diseases such as heart failure and chronic kidney disease (CKD), where new drugs are approved only once every two decades. This bench-to-bedside-and-back-to-bench model is more effective than the mainstream approach that begins with gene-knockout targets in animals. It is hoped that this discovery will lead to newer medications for patients with chronic diseases.Bio ValleyBioon.com）