CANVAS: Canagliflozin improved renal outcomes in diabetes

AUSTIN, TEX. – Canagliflozin can improve renal outcomes in patients with type 2 diabetes, even when they have mild or moderate kidney disease, new data from the CANVAS program suggested.

“The effect of canagliflozin on composite renal outcomes was large, particularly in people with preserved kidney function,” Brendon L. Neuen, MBBS, of University of New South Wales, Sydney, and his associates wrote in a poster. Baseline renal function also did not appear to affect the safety of canagliflozin, the investigators reported at a meeting sponsored by the National Kidney Foundation.

In patients with diabetes mellitus, increased proximal reabsorption of glucose and sodium decreases the amount of sodium reaching the macula densa in the distal convoluted tubule. This results in reduced use of adenosine triphosphate for sodium reabsorption, which thereby decreases adenosine release and vasoconstriction of afferent arterioles. Left unchecked, this dampening of the tubuloglomerular feedback mechanism increases glomerular filtration and leads to diabetic nephropathy.

Sodium glucose cotransporter 2 (SGLT2) inhibitors such as canagliflozin (Invokana) and empagliflozin (Jardiance) help mitigate this pathology by vasoconstricting afferent arterioles. Previously, in an exploratory analysis of the multicenter, placebo-controlled EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) trial, empagliflozin led to modest but statistically significant long-term reductions in urinary albumin secretion for diabetic patients, regardless of their baseline urinary albumin to creatinine ratio (Lancet Diabetes Endocrinol. 2017 Aug;5[8]:610-21). Treatment with empagliflozin also significantly reduced the risk of developing microalbuminuria or macroalbuminuria (P less than .0001).

The multicenter, double-blind, placebo-controlled CANVAS (Canagliflozin Cardiovascular Assessment Study) and CANVAS-R (A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants with Type 2 Diabetes Mellitus) trials included more than 10,000 adults with type 2 diabetes and high cardiovascular risk. In the primary analysis, canagliflozin significantly reduced the risk of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke compared with placebo (N Engl J Med. 2017 Aug 17;377[7]:644-57).

Dr. Neuen and his associates compared the effects of canagliflozin on renal outcomes and safety among CANVAS patients whose estimated glomerular filtration rate (eGFR) was preserved (greater than 60 mL/min per 1.73 m²) or reduced (less than 60 ml/min per 1.73 m²). Actual mean eGFRs in each of these groups were 83 mL/min per 1.73 m² and 49 mL/min per 1.73 m², respectively. Compared with placebo, canagliflozin acutely reduced eGFR in patients with either preserved (average, –2.2 mL/min per 1.73 m²) or reduced (–2.83 mL/min/1.73 m² ) baseline kidney function (P = 0.21).

 

Among patients with preserved function at baseline, canagliflozin was associated with a statistically significant 47% decrease in risk of renal death, end-stage kidney disease, or a 40% or greater drop in eGFR (hazard ratio, 0.53; 95% confidence interval, 0.39-0.73). Canagliflozin also showed renal benefits for patients with reduced kidney function, but the effect did not reach statistical significance (HR, 0.76; 95% CI, 0.49-1.17). Findings were similar when the researchers tweaked the composite renal endpoint by replacing the eGFR criterion with doubling of serum creatinine (HR, 0.42; 95% CI, 0.23-0.75 and HR, 0.81; 95% CI, 0.37-1.77, respectively).

Canagliflozin has a black box warning for amputation risk. There was no indication that early renal function further increased this risk, the researchers reported. CANVAS patients who received canagliflozin underwent amputations (usually at the level of the toe or metatarsal) at rates of 6.3 per 1,000 person-years overall, 5.6 per 1,000 person-years in the setting of preserved kidney function, and 9.9 per 1,000 person-years in the setting of reduced kidney function. Rates in the placebo group were 3.4, 3.0, and 4.8 amputations per 1,000 person-years, respectively. Additionally, baseline renal status did not significantly affect risk of fracture, serious kidney-related adverse events, or serious acute kidney injury. Patients with baseline renal insufficiency were at increased risk of developing serious hyperkalemia (HR, 2.11; P = .06), but these events were uncommon in both treatment groups.

No CANVAS patient had stage 4 or worse kidney disease (eGFR less than 30 mL/min per 1.73 m²) at enrollment, the researchers noted. The ongoing phase 3 CREDENCE (Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation) trial will shed more light on canagliflozin in the setting of renal disease, they added. This multicenter, double-blind trial compares canagliflozin with placebo in more than 4,000 patients with diabetic nephropathy. Results are expected in 2019.

Janssen funded the CANVAS and CANVAS-R trials. Disclosures were not provided.

SOURCE: Neuen BL et al. SCM 2018.
 

AUSTIN, TEX. – Canagliflozin can improve renal outcomes in patients with type 2 diabetes, even when they have mild or moderate kidney disease, new data from the CANVAS program suggested.

“The effect of canagliflozin on composite renal outcomes was large, particularly in people with preserved kidney function,” Brendon L. Neuen, MBBS, of University of New South Wales, Sydney, and his associates wrote in a poster. Baseline renal function also did not appear to affect the safety of canagliflozin, the investigators reported at a meeting sponsored by the National Kidney Foundation.

In patients with diabetes mellitus, increased proximal reabsorption of glucose and sodium decreases the amount of sodium reaching the macula densa in the distal convoluted tubule. This results in reduced use of adenosine triphosphate for sodium reabsorption, which thereby decreases adenosine release and vasoconstriction of afferent arterioles. Left unchecked, this dampening of the tubuloglomerular feedback mechanism increases glomerular filtration and leads to diabetic nephropathy.

Sodium glucose cotransporter 2 (SGLT2) inhibitors such as canagliflozin (Invokana) and empagliflozin (Jardiance) help mitigate this pathology by vasoconstricting afferent arterioles. Previously, in an exploratory analysis of the multicenter, placebo-controlled EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) trial, empagliflozin led to modest but statistically significant long-term reductions in urinary albumin secretion for diabetic patients, regardless of their baseline urinary albumin to creatinine ratio (Lancet Diabetes Endocrinol. 2017 Aug;5[8]:610-21). Treatment with empagliflozin also significantly reduced the risk of developing microalbuminuria or macroalbuminuria (P less than .0001).

The multicenter, double-blind, placebo-controlled CANVAS (Canagliflozin Cardiovascular Assessment Study) and CANVAS-R (A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants with Type 2 Diabetes Mellitus) trials included more than 10,000 adults with type 2 diabetes and high cardiovascular risk. In the primary analysis, canagliflozin significantly reduced the risk of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke compared with placebo (N Engl J Med. 2017 Aug 17;377[7]:644-57).

Dr. Neuen and his associates compared the effects of canagliflozin on renal outcomes and safety among CANVAS patients whose estimated glomerular filtration rate (eGFR) was preserved (greater than 60 mL/min per 1.73 m²) or reduced (less than 60 ml/min per 1.73 m²). Actual mean eGFRs in each of these groups were 83 mL/min per 1.73 m² and 49 mL/min per 1.73 m², respectively. Compared with placebo, canagliflozin acutely reduced eGFR in patients with either preserved (average, –2.2 mL/min per 1.73 m²) or reduced (–2.83 mL/min/1.73 m² ) baseline kidney function (P = 0.21).

 

Among patients with preserved function at baseline, canagliflozin was associated with a statistically significant 47% decrease in risk of renal death, end-stage kidney disease, or a 40% or greater drop in eGFR (hazard ratio, 0.53; 95% confidence interval, 0.39-0.73). Canagliflozin also showed renal benefits for patients with reduced kidney function, but the effect did not reach statistical significance (HR, 0.76; 95% CI, 0.49-1.17). Findings were similar when the researchers tweaked the composite renal endpoint by replacing the eGFR criterion with doubling of serum creatinine (HR, 0.42; 95% CI, 0.23-0.75 and HR, 0.81; 95% CI, 0.37-1.77, respectively).

Canagliflozin has a black box warning for amputation risk. There was no indication that early renal function further increased this risk, the researchers reported. CANVAS patients who received canagliflozin underwent amputations (usually at the level of the toe or metatarsal) at rates of 6.3 per 1,000 person-years overall, 5.6 per 1,000 person-years in the setting of preserved kidney function, and 9.9 per 1,000 person-years in the setting of reduced kidney function. Rates in the placebo group were 3.4, 3.0, and 4.8 amputations per 1,000 person-years, respectively. Additionally, baseline renal status did not significantly affect risk of fracture, serious kidney-related adverse events, or serious acute kidney injury. Patients with baseline renal insufficiency were at increased risk of developing serious hyperkalemia (HR, 2.11; P = .06), but these events were uncommon in both treatment groups.

No CANVAS patient had stage 4 or worse kidney disease (eGFR less than 30 mL/min per 1.73 m²) at enrollment, the researchers noted. The ongoing phase 3 CREDENCE (Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation) trial will shed more light on canagliflozin in the setting of renal disease, they added. This multicenter, double-blind trial compares canagliflozin with placebo in more than 4,000 patients with diabetic nephropathy. Results are expected in 2019.

Janssen funded the CANVAS and CANVAS-R trials. Disclosures were not provided.

SOURCE: Neuen BL et al. SCM 2018.
 

AUSTIN, TEX. – Canagliflozin can improve renal outcomes in patients with type 2 diabetes, even when they have mild or moderate kidney disease, new data from the CANVAS program suggested.

“The effect of canagliflozin on composite renal outcomes was large, particularly in people with preserved kidney function,” Brendon L. Neuen, MBBS, of University of New South Wales, Sydney, and his associates wrote in a poster. Baseline renal function also did not appear to affect the safety of canagliflozin, the investigators reported at a meeting sponsored by the National Kidney Foundation.

In patients with diabetes mellitus, increased proximal reabsorption of glucose and sodium decreases the amount of sodium reaching the macula densa in the distal convoluted tubule. This results in reduced use of adenosine triphosphate for sodium reabsorption, which thereby decreases adenosine release and vasoconstriction of afferent arterioles. Left unchecked, this dampening of the tubuloglomerular feedback mechanism increases glomerular filtration and leads to diabetic nephropathy.

Sodium glucose cotransporter 2 (SGLT2) inhibitors such as canagliflozin (Invokana) and empagliflozin (Jardiance) help mitigate this pathology by vasoconstricting afferent arterioles. Previously, in an exploratory analysis of the multicenter, placebo-controlled EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) trial, empagliflozin led to modest but statistically significant long-term reductions in urinary albumin secretion for diabetic patients, regardless of their baseline urinary albumin to creatinine ratio (Lancet Diabetes Endocrinol. 2017 Aug;5[8]:610-21). Treatment with empagliflozin also significantly reduced the risk of developing microalbuminuria or macroalbuminuria (P less than .0001).

The multicenter, double-blind, placebo-controlled CANVAS (Canagliflozin Cardiovascular Assessment Study) and CANVAS-R (A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants with Type 2 Diabetes Mellitus) trials included more than 10,000 adults with type 2 diabetes and high cardiovascular risk. In the primary analysis, canagliflozin significantly reduced the risk of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke compared with placebo (N Engl J Med. 2017 Aug 17;377[7]:644-57).

Dr. Neuen and his associates compared the effects of canagliflozin on renal outcomes and safety among CANVAS patients whose estimated glomerular filtration rate (eGFR) was preserved (greater than 60 mL/min per 1.73 m²) or reduced (less than 60 ml/min per 1.73 m²). Actual mean eGFRs in each of these groups were 83 mL/min per 1.73 m² and 49 mL/min per 1.73 m², respectively. Compared with placebo, canagliflozin acutely reduced eGFR in patients with either preserved (average, –2.2 mL/min per 1.73 m²) or reduced (–2.83 mL/min/1.73 m² ) baseline kidney function (P = 0.21).

 

Among patients with preserved function at baseline, canagliflozin was associated with a statistically significant 47% decrease in risk of renal death, end-stage kidney disease, or a 40% or greater drop in eGFR (hazard ratio, 0.53; 95% confidence interval, 0.39-0.73). Canagliflozin also showed renal benefits for patients with reduced kidney function, but the effect did not reach statistical significance (HR, 0.76; 95% CI, 0.49-1.17). Findings were similar when the researchers tweaked the composite renal endpoint by replacing the eGFR criterion with doubling of serum creatinine (HR, 0.42; 95% CI, 0.23-0.75 and HR, 0.81; 95% CI, 0.37-1.77, respectively).

Canagliflozin has a black box warning for amputation risk. There was no indication that early renal function further increased this risk, the researchers reported. CANVAS patients who received canagliflozin underwent amputations (usually at the level of the toe or metatarsal) at rates of 6.3 per 1,000 person-years overall, 5.6 per 1,000 person-years in the setting of preserved kidney function, and 9.9 per 1,000 person-years in the setting of reduced kidney function. Rates in the placebo group were 3.4, 3.0, and 4.8 amputations per 1,000 person-years, respectively. Additionally, baseline renal status did not significantly affect risk of fracture, serious kidney-related adverse events, or serious acute kidney injury. Patients with baseline renal insufficiency were at increased risk of developing serious hyperkalemia (HR, 2.11; P = .06), but these events were uncommon in both treatment groups.

No CANVAS patient had stage 4 or worse kidney disease (eGFR less than 30 mL/min per 1.73 m²) at enrollment, the researchers noted. The ongoing phase 3 CREDENCE (Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation) trial will shed more light on canagliflozin in the setting of renal disease, they added. This multicenter, double-blind trial compares canagliflozin with placebo in more than 4,000 patients with diabetic nephropathy. Results are expected in 2019.

Janssen funded the CANVAS and CANVAS-R trials. Disclosures were not provided.

SOURCE: Neuen BL et al. SCM 2018.