Janssen Pharmaceuticals, a subsidiary of U.S. pharmaceutical giant Johnson & Johnson (JNJ), recently announced important new analysis results from the landmark Phase III CREDENCE study, demonstrating that the SGLT2 inhibitor Invokana (canagliflozin) consistently reduced the risk of renal and cardiovascular (CV) events across patients with varying levels of renal function or estimated glomerular filtration rate (eGFR). The analysis indicated that Invokana provided robust and consistent safety and efficacy across all tested eGFR levels. Notably, greater absolute renal benefits were observed in patients with advanced renal impairment (eGFR <60 mL/min/1.73 m²). These secondary analysis results were presented at the American Society of Nephrology’s (ASN) Kidney Week 2019.
Renal failure is a serious concern for patients with type 2 diabetes (T2D) and diabetic nephropathy (DN; also known as diabetic kidney disease, DKD). This latest analysis confirms that Invokana can slow the progression of renal failure and benefit patients, regardless of their level of renal function. Invokana is the only diabetes medication that slows the progression of DKD and reduces the risk of hospitalization for heart failure in patients with T2D and DKD.
In September this year, Invokana received approval from the U.S. FDA for a new indication: to reduce the risk of end-stage kidney disease (ESKD), worsening kidney function, cardiovascular (CV) death, and hospitalization for heart failure in adult patients with type 2 diabetes (T2D) and diabetic kidney disease (DKD) who have a certain amount of protein in their urine. This approval was based on data from CREDENCE, the only completed renal outcomes study in diabetes medicine. In July 2018, the study was terminated early after meeting pre-specified efficacy criteria.
With this approval, Invokana is the only type 2 diabetes medication indicated to reduce the risk of heart failure hospitalization in patients with both T2D and DKD, as well as the first new drug in nearly 20 years indicated to delay the progression of DKD in this patient population.
CREDENCE was the first rigorously designed renal outcomes study conducted in patients with type 2 diabetes (T2D) and diabetic kidney disease (DKD) receiving standard-of-care background therapy, including 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 chronic kidney disease (CKD) to evaluate the efficacy and safety of canagliflozin 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 have been treated with the maximum labeled or tolerated dose of an ACE inhibitor or ARB for at least 4 weeks prior to randomization.
Prespecified interim analysis data showed that Invokana 100 mg plus standard of care reduced the risk of the primary composite endpoint (end-stage kidney disease [ESKD], doubling of serum creatinine, or renal or cardiovascular death) by 30% compared with placebo plus standard of care. Additionally, the results demonstrated that Invokana reduced the risk of secondary cardiovascular endpoints, including a 39% reduction in the risk of hospitalization for heart failure. Overall, the incidence of adverse events and serious adverse events was similar but numerically lower in the Invokana treatment group compared with the placebo group. The rates of diabetic ketoacidosis and genital fungal infections were numerically higher in the Invokana treatment group than in other clinical trials. Furthermore, there was no imbalance in lower-limb amputations or fractures in this study, and no new safety signals were identified.
In this prespecified secondary analysis presented at the ASN meeting, CREDENCE investigators examined whether the effects of Invokana on clinically important outcomes were consistent across patients with varying baseline eGFR levels. Among the 4,401 enrolled patients, 1,313 (30%) had moderate to severe renal impairment (eGFR 30 to <45 mL/min/1.73 m²), 1,279 (29%) had mild to moderate renal impairment (eGFR 45 to <60 mL/min/1.73 m²), and 1,809 (41%) had mild renal impairment (eGFR 60 to <90 mL/min/1.73 m²). The analysis results were consistent with those of the primary study, with the following observations:
—Invokana consistently reduced the risk of cardiovascular (CV) and renal events across all eGFR subgroups (all p-interaction > 0.11). The absolute incidence rates of CV and renal events were associated with eGFR levels, with higher event rates observed as eGFR declined. The absolute benefits of Invokana on renal and CV outcomes were generally greater in subgroups with lower eGFR (particularly eGFR 30 to <45 and eGFR 45 to <60 mL/min/1.73 m²).
—In patients with an eGFR of 30 to <45 mL/min/1.73 m², Invokana reduced the primary composite endpoint by 25% compared with placebo (event rates: 72.2 vs. 95.4 per 1,000 patient-years; HR=0.75; 95% CI: 0.59–0.95) and reduced the kidney-specific composite endpoint by 29% (event rates: 51.6 vs. 71.7 per 1,000 patient-years; HR=0.71; 95% CI: 0.53–0.94).
— In particular, compared with placebo, Invokana reduced the composite endpoint of cardiovascular (CV) death or hospitalization for heart failure (HHF) by 31% (event rates: 40.7 vs. 59.1 per 1,000 patients; HR=0.69, 95% CI: 0.50–0.94), and reduced the HHF endpoint by 30% (event rates: 22.8 vs. 32.3 per 1,000 patient-years). Furthermore, compared with placebo, Invokana reduced the composite endpoint of CV death, myocardial infarction, or stroke by 23% (event rates: 47.2 vs. 61.7 per 1,000 patient-years; HR=0.77, 95% CI: 0.57–1.03).
—Adverse events and serious adverse events associated with Invokana were generally infrequent, consistent with the results observed in eGFR subgroups at screening (p for interaction: 0.40 and 0.15, respectively). The incidence of specific adverse events, including fractures, amputations, and urinary tract infections, was generally similar between participants randomized to receive Invokana or placebo, with consistent findings across eGFR subgroups.
—Compared with placebo, Invokana reduced glycated hemoglobin (A1c), blood pressure, body weight, and proteinuria across all eGFR subgroups.
In this analysis, at Week 3, Invokana caused an acute decline in eGFR, which was significant in each eGFR subgroup (all p < 0.001), indicating a favorable response to the initiation of Invokana treatment. After Week 3, Invokana resulted in a slower rate of eGFR decline compared with the placebo group across all eGFR categories (all p < 0.001).
Researchers also examined patients whose eGFR was below 30 mL/min/1.73 m² at the end of the study (N=929; Invokana n=417, placebo n=512). The mean follow-up time to the first occurrence of eGFR below 30 mL/min/1.73 m² was 12.9 months (11.7 months for Invokana; 13.8 months for placebo), and the mean follow-up time thereafter was 19.3 months (20.5 months for Invokana; 18.4 months for placebo).
Meg J. Jardine, Associate Professor at the University of New South Wales Faculty of Medicine and a CREDENCE study investigator, stated, “We now know that the renal and cardiovascular benefits of canagliflozin are preserved across a broad eGFR range of 90–30 mL/min/1.73 m². Because these patients are at higher risk at baseline, the absolute benefit in preventing progression of kidney disease is greater for those who already have renal impairment. Importantly, there were no differences in safety as eGFR declined, which will provide physicians with greater confidence when prescribing the medication across the widest possible range of eGFR levels.”
Canagliflozin (卡格列净): Marketed in China under the brand name Invokana®
Canagliflozin is a novel glucose-lowering agent belonging to the class of sodium-glucose cotransporter 2 (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 glucose-lowering effect is independent of beta-cell function and insulin resistance. Compared with non-diabetic individuals, patients with type 2 diabetes exhibit increased renal reabsorption of glucose into the bloodstream, which may contribute to elevated blood glucose levels. In addition to its established glucose-lowering efficacy, canagliflozin offers additional benefits, including weight reduction, attenuation of proteinuria progression, and blood pressure lowering.
Currently, the indications for Invokana are: (1) to lower blood glucose levels in adult patients with type 2 diabetes mellitus, in conjunction with diet and exercise; (2) to reduce the risk of major adverse cardiovascular events, such as myocardial infarction, stroke, and death, in adult patients with type 2 diabetes mellitus and established cardiovascular disease; (3) to reduce the risk of end-stage kidney disease (ESKD), deterioration of renal function, cardiovascular death, and hospitalization for heart failure in adult patients with type 2 diabetes mellitus and diabetic nephropathy who have albuminuria.
Invokana is not indicated for patients with type 1 diabetes or for patients with diabetic ketoacidosis. The safety and efficacy of this medication in children under 18 years of age have not been established.
In the Chinese market, canagliflozin was approved in September 2017 under the brand name Invokana®. When glycemic control is inadequate with metformin monotherapy or with the combination of metformin and a sulfonylurea, Invokana may be used in conjunction with diet and exercise, either in combination with metformin or with metformin and a sulfonylurea, to improve glycemic control in adult patients with type 2 diabetes mellitus.
Original Source: New Analysis from Landmark CREDENCE Study Shows the Efficacy and Safety Profiles of INVOKANA® (canagliflozin) are Consistent Across Various Levels of Kidney Function
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