First-in-20-Years Antidiabetic Drug to Reduce Kidney and Cardiovascular Risks: Janssen Announces Canagliflozin Efficacy from CREDENCE Trial

Janssen Pharmaceuticals, a subsidiary of the US pharmaceutical company Johnson & Johnson (JNJ), recently announced detailed data from CREDENCE, a landmark Phase III clinical study evaluating the renal outcomes of the glucose-lowering drug Invokana (Yi Ke An; generic name: canagliflozin), at the 2019 World Congress of Nephrology (WCN) annual meeting of the International Society of Nephrology (ISN) held in Melbourne, Australia. The results showed that in type 2 diabetes patients with chronic kidney disease (CKD),DiabetesIn patients with type 2 diabetes (T2D), when added to standard of care, Invokana significantly reduced the risk of the primary composite renal endpoint and the secondary cardiovascular endpoint compared with placebo. Importantly, the study showed no imbalance in amputations and fractures. Furthermore, no new safety concerns were identified in this study of high-risk patients.

According to this study, Invokana is the first and only agent in nearly 20 years that can significantly reduce the risk of kidney failure, dialysis, or kidney transplantation, as well as renal or cardiovascular (CV) death, in this high-risk patient population.DiabetesDrug.

CREDENCE (NCT02065791) was the first rigorously designed renal outcomes study conducted in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) receiving standard-of-care background therapy, which included angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). This randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial enrolled 4,400 patients with T2D and CKD to evaluate the efficacy and safety of Invokana versus placebo in preventing clinically important renal and cardiovascular (CV) outcomes. Eligible patients had an estimated glomerular filtration rate (eGFR) ≥30 and <90 mL/min/1.73 m² and albuminuria (urine albumin-to-creatinine ratio >300 mg/g and ≤5,000 mg/g). All patients were required to receive ACE inhibitors or ARBs at the maximum labeled or tolerated dose for more than 4 weeks prior to randomization.

In July 2018, the Independent Data Monitoring Committee (IDMC) reviewed the data from a pre-specified interim analysis. The results demonstrated that Invokana plus standard of care met the pre-specified efficacy criteria for the primary composite endpoint compared with placebo plus standard of care. The primary composite endpoint included progression to end-stage kidney disease (ESKD; defined as initiation of dialysis or kidney transplantation), a doubling of serum creatinine (a key predictor of ESKD), and renal or cardiovascular (CV) death. Based on the IDMC’s recommendation, Johnson & Johnson decided to terminate the study early.

This timeMeetingThe detailed results published above showed that, compared with placebo plus standard care, Invokana plus standard care significantly reduced the risk of the primary composite endpoint by 30% (HR: 0.70; 95% CI: 0.59–0.82; p < 0.0001). These findings were consistent across all components of the primary composite endpoint and in all 15 prespecified patient subgroups. Notably, Invokana reduced the risk of end-stage kidney disease (ESKD) by 32% (HR: 0.68; 95% CI: 0.54–0.86; p = 0.0015).

In addition, Invokana also demonstrated a secondary endpoint of major adverse cardiovascular events (MACE) (consisting of non-fatalMyocardial Infarction, the risk of nonfatal stroke and cardiovascular death was reduced by 20% (HR: 0.80; 95% CI: 0.67-0.95; p=0.0121), the risk of the composite endpoint of cardiovascular death and heart failure hospitalization was reduced by 31% (HR: 0.69; 95% CI: 0.57-0.83; p<0.0001), and the risk of heart failure hospitalization was reduced by 39% (HR: 0.61; 95% CI: 0.47-0.80; p=0.0003).

Compared with placebo, patients treated with Invokana had numerically lower incidence rates of adverse events and serious adverse events. No differences were observed in the incidence of amputation (HR: 1.11; 95% CI: 0.79–1.56) or adjudicated fractures (HR: 0.98; 95% CI: 0.70–1.37).

Vlado Perkovic, Professor of Medicine at the University of New South Wales in Australia and Co-Chair of the CREDENCE Study Steering Committee, stated, “Invokana represents the first breakthrough in medicine in nearly two decades, demonstrating a significant delay in CKD progression among patients with type 2 diabetes (T2D) at high risk for kidney failure. These impressive results from the CREDENCE study have important clinical implications for preventing kidney failure and improving the health of millions of patients with both CKD and T2D.”

Dr. James List, Global Therapeutic Area Head of R&D at Janssen, stated, “Diabetesis the leading cause of kidney failure in millions of people worldwide, and the clear need for new treatment options was the impetus for initiating the CREDENCE study. Today, we are pleased to share the study results, which have the potential to establish Invoana as the only medication that, when added to the current standard of care, can safely reduce the risk of kidney failure in this high-risk patient population. Currently, we are working with the United StatesFDAand work closely with health authorities around the world to bring this important medicine to patients with life-threatening conditions.”

The active pharmaceutical ingredient of Invokana is canagliflozin, a novel hypoglycemic agent belonging to the class of SGLT2 inhibitors. SGLT2 is a transporter protein involved in glucose reabsorption in the proximal renal tubules of the kidney. Canagliflozin primarily lowers blood glucose levels by inhibiting SGLT2 expressed in the kidneys, thereby reducing renal glucose reabsorption and increasing urinary glucose excretion. This hypoglycemic effect is independent of β-cell function and insulin resistance. Unlike non-DiabetesCompared with the general population, the kidneys of patients with type 2 diabetes can reabsorb large amounts of glucose into the bloodstream, which may elevate blood glucose levels. In addition to its clear glucose-lowering effects, canagliflozin provides additional benefits such as weight reduction, slowing the progression of proteinuria, and lowering blood pressure.

In the United States, Invokana was approved in March 2013FDAApproved as the first SGLT2 inhibitor-class glucose-lowering drug to be marketed globally, it has currently received approval in multiple countries worldwide. The indications for this drug are: 1) to lower blood glucose levels in patients with type 2 diabetes in conjunction with diet and exercise; 2) to reduce the risk of heart disease in adult patients with type 2 diabetes who have pre-existing cardiovascular disease,Strokeor the risk of major adverse cardiovascular events such as death. It should be noted that this drug is not indicated for patients with type 1 diabetes or diabetic ketoacidosis.

Kidney disease is a well-recognized complication of diabetes, and diabetes is also the most common cause of kidney failure. It is estimated that up to 40% of patients with diabetes will develop nephropathy. Currently, multiple pharmaceutical companies are conducting studies on the renal outcomes of SGLT2 inhibitor-class glucose-lowering drugs, in addition to Johnson & Johnson,Eli Lilly- Boehringer Ingelheim Diabetes Alliance Jardiance (empagliflozin, empagliflozin) andAstraZenecaThe Phase III renal outcome study of Farxiga (dapagliflozin) is underway, with Jardiance’s data to be released in 18 months, while Farxiga is expected to announce its results in the fall of 2020.

In late March this year, Johnson & Johnson, based on the results of the CREDENCE study, submitted to the U.S.FDASubmitted a new indication application for Invokana: to reduce the risk of end-stage kidney disease (ESKD) in adult patients with type 2 diabetes and chronic kidney disease (CKD). If approved, Invokana will become the first and only drug in the past 20 years that, when used in combination with standard care, can significantly reduce the risk of ESKD in patients with type 2 diabetes, providing an important new treatment option for millions of patients worldwide suffering from these conditions.

Analysts have stated that if Invokana’s new indication is approved, it is expected to significantly boost the drug’s sales. According to released performance data, Invokana’s revenue declined to $881 million in 2018, while Farxiga’s sales surged to $1.39 billion, and Jardiance grew by 47% to $658 million.BioValleyBioon.com）