Janssen announced additional analyses from the CANVAS clinical trial program showing INVOKANA (canagliflozin) improved renal outcomes and demonstrated potential renal protective effects in patients with type 2 diabetes mellitus (T2DM), who either have, or are at risk for, cardiovascular (CV) disease.
The renal analyses showed that compared to placebo, canagliflozin reduced the risk of kidney disease progression, including significantly reducing urinary albumin excretion and stabilizing estimated glomerular filtration rate (eGFR) over a study duration of more than six years:
Canagliflozin reduced the rates of several pre-specified major renal composite endpoints by up to 47 percent, such as end-stage kidney disease (ESKD), doubled serum creatinine (dSCr) or renal death (HR: 0.53, 95% CI: 0.33 to 0.84).
Urinary albumin excretion was 18 percent lower in all participants treated with canagliflozin compared with placebo (HR: 0.82; 95% CI: 0.16 to 0.20). It was 34 percent lower (HR: 0.66; 95% CI: 0.29 to 0.38) in participants with baseline microalbuminuria and 36 percent lower (HR: 0.64; 95% CI: 0.28 to 0.43) in those participants with baseline macroalbuminuria. Median urinary albumin to creatinine ratio (UACR) was 12.3 mg/g.
Participants treated with canagliflozin experienced an initial decline in mean eGFR; thereafter, that rate gradually increased over the study duration (6.5 years). In contrast, participants treated with placebo experienced a progressive decline in eGFR. Mean baseline eGFR was 76.5 mL/min/1.73 m2.
There was no increase in renal adverse events (serious or non-serious) compared to placebo, including acute kidney injury and hyperkalemia.
INVOKANA demonstrated consistent improvement of renal outcomes across multiple composite endpoints that were independently confirmed by an Endpoints Adjudication Committee.
"Millions of people around the world suffer from diabetic kidney disease, which will affect nearly one-third of all type 2 diabetes patients and is the most common cause of kidney failure in most countries.i This underscores the need to identify new treatment options for these people who have not seen an innovation in the space in the last 20 years," said Vlado Perkovic, M.B.B.S, Ph.D., F.A.S.N., F.R.A.C.P., Professor of Medicine, University of New South Wales Sydney, and Executive Director, The George Institute for Global Health. "New data from the CANVAS Program clearly indicate better renal outcomes for people treated with canagliflozin, and suggest that this agent protects kidney function, in addition to providing previously presented cardiovascular benefits."
The CANVAS Program is the longest, largest and broadest completed CV outcomes program of any sodium glucose cotransporter 2 (SGLT2) inhibitor, to date, and was the first program to assess the efficacy, safety, and durability of canagliflozin in more than 10,000 patients with T2DM who had either a prior history of CV disease or at least two CV risk factors. The data from the integrated analysis of the CANVAS and CANVAS-R trials were presented earlier this year in a special symposium at the American Diabetes Association 77th Scientific Sessions on June 12 in San Diego, CA, and simultaneously published in the New England Journal of Medicine. The results from the integrated analysis showed canagliflozin significantly reduced the combined risk of CV death, myocardial infarction (MI), and nonfatal stroke versus placebo in patients with T2DM at risk for, or with a history of, CV disease. Additional analysis revealed canagliflozin treatment was associated with a reduced risk for hospitalization for heart failure and demonstrated potential renal protective effects.
The ongoing, fully enrolled CREDENCE trial, the first dedicated SGLT2 inhibitor Phase 3 renal outcomes trial, is evaluating the effects of canagliflozin on renal outcomes in patients with T2DM and kidney disease.
No new adverse events were observed during this additional analysis than were previously reported from the CANVAS Program.
The CANVAS Program is composed of two nearly-identical large outcomes studies: CANVAS (CANagliflozin CardioVascular Assessment Study (NCT01032629) and CANVAS-R (Study of the Effects of Canagliflozin on Renal Endpoints in Adult Subjects with T2DM, (NCT01989754).
The CANVAS Program is the largest completed CV outcomes program of any SGLT2 inhibitor to date, with a total of 10,142 patients – 4,330 patients in CANVAS and 5,812 patients in CANVAS-R. In the randomized, placebo-controlled Phase 3/4 studies, a vast majority of patients were obese, with a history of hypertension, 66 percent of patients had a history of CV disease (14 percent had a history of heart failure), and 34 percent of patients had at least two CV risk factors. The study assessed the safety of canagliflozin relative to placebo in patients receiving specific commonly-used diabetes agents. The primary endpoint was defined as major adverse CV events (MACE), composed of nonfatal MI, nonfatal stroke, and CV death, and the secondary endpoint was defined as progression of albuminuria, beta-cell function, eGFR changes and UACR.
In the CANVAS study, patients were randomly assigned in a 1:1:1 ratio to placebo, canagliflozin 100mg and canagliflozin 300mg. The mean and median exposure to investigational product was approximately 4.3 and 5.8 years, respectively. The mean and median follow-up time was 5.7 and 6.1 years, respectively.
In the CANVAS-R study, patients were randomly assigned in a 1:1 ratio to placebo or canagliflozin 100mg (with an investigator option to up-titrate to 300mg if the patient required additional glycemic control, provided the 100mg dosage was well tolerated). The mean and median exposure to investigational product was approximately 1.8 and 1.9 years, respectively. The mean and median follow-up time was 2.1 years.
These CANVAS and CANVAS-R studies were designed to be highly similar in patient population, procedures and assessments, evaluating the effects of canagliflozin on CV events in a similar study population. This approach is demonstrated in three published studies: "Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)—A randomized placebo-controlled trial," published online by American Heart Journal; "Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study–Renal (CANVAS-R): A randomized, placebo-controlled trial," published online by Diabetes, Obesity and Metabolism; and "Optimizing the analysis strategy for the CANVAS Program – a pre-specified plan for the integrated analyses of the CANVAS and CANVAS-R trials," published online by Diabetes, Obesity and Metabolism.