Perspective

Canagliflozin reduces risk for CVD, kidney disease in adults with type 2 diabetes

Patients with type 2 diabetes at high risk for cardiovascular disease assigned the SGLT2 inhibitor canagliflozin showed a 33% reduction in risk for hospitalization for heart failure and were 40% less likely to experience renal decline vs. those assigned placebo, according to findings from the integrated CANVAS study presented at the American Diabetes Association Scientific Sessions.

In a randomized, double blind, placebo-controlled trial conducted across 30 countries, researchers also noted that participants assigned canagliflozin (Invokana, Janssen) were twice as likely to experience an amputation, primarily at the toe or metatarsal, compared with those receiving placebo.

“The key question is: How do the risks and the benefits balance up?” Bruce Neal, MB, ChB, PhD, scientific director at The George Institute for Global Health, said during a press conference announcing the findings. “For 1,000 individuals treated [with canagliflozin] for 5 years ... there would be 23 fewer deaths from vascular disease, 17 fewer hospitalizations for heart failure and 16 fewer serious declines in renal function. By contrast, there would be 15 more amputations, and 10 of these would be at the toe or forefoot and five [would be] above the ankle.”

Study design, results

For the integrated CANVAS program, Neal and colleagues analyzed data from two trials involving 10,142 participants with type 2 diabetes and high CV risk, CANVAS (n = 4,330) and CANVAS-R (n = 5,812). The mean age for both trials was 63 years; 35.8% were women; mean duration of diabetes was 13.5 years; mean HbA1c, 8.2%; mean estimated glomerular filtration rate was 76.5 mL/min/1.73 m²; median urinary albumin to creatinine ratio was 12.3. Researchers randomly assigned participants in CANVAS to 100 mg or 300 mg canagliflozin or placebo; participants in CANVAS-R received an initial dose of 100 mg canagliflozin daily with an optional increase to 300 mg at week 13, or matching placebo. Follow-up occurred every 3 months for the first year and at 6-month intervals thereafter, with follow-up by telephone between in-person appointments. Serum creatinine and eGFR rate were measured at least every 26 weeks in both trials; urinary albumin to creatinine ratio was assessed every 26 weeks in CANVAS-R and at week 12 and annually in CANVAS. Primary outcome was a composite of death from CVD, nonfatal myocardial infarction and nonfatal stroke. Final follow-up occurred in February.

Within the cohort, 9,734 participants completed the trials; mean follow-up for both trials was 188.2 weeks, with a longer follow-up period in the CANVAS study (mean, 295.9 weeks). At baseline, 65.6% of participants had a history of CVD, 22.6% had microalbuminuria and 7.6% had macroalbuminuria.

Researchers found that the rate of primary outcome was lower in participants assigned canagliflozin vs. placebo, occurring in 26.9 per 1,000 patient-years vs. 31.5 per 1,000 patient-years (HR = 0.86; 95% CI, 0.75-0.97).

Researchers also observed a possible benefit with respect to progression to albuminuria in the canagliflozin group (HR = 0.73; 95% CI, 0.67-0.79), as well as the composite outcome of a sustained 40% reduction in GFR, need for renal replacement therapy or renal death (HR = 0.6; 95% CI, 0.47-0.77).

Possible class effect

David R. Matthews

The findings from the integrated CANVAS study echo those from another study involving an SGLT2 inhibitor that initially surprised investigators. In the EMPA-REG Outcome trial, a randomized, double blind, placebo-controlled trial in 42 countries, researchers found that empagliflozin (Jardiance, Boehringer Ingelheim), when combined with standard care, reduced the risk for CV death by 38% compared with placebo in patients with type 2 diabetes with established vascular disease, with no significant difference in the risk for nonfatal MI or stroke. Patients treated with empagliflozin also experienced a 32% reduction in all-cause mortality risk and a 35% reduction in risk for hospitalization for heart failure, according to researchers. Within the EMPA-REG cohort (n = 7,020), 76% of participants had an established history of coronary artery disease; 46% of participants had a history of MI; between 9.5% and 10.5% of participants had a history of cardiac failure.

The EMPA-REG Outcome results, presented in September 2015, surprised researchers, who predicted CV-neutral results going into the study.

“There is obviously interest in interpreting [CANVAS] data in the context of the EMPA-REG Outcome [trial],” David R. Matthews, DPhil, FRCP, professor of diabetic medicine at the University of Oxford, said during a symposium discussing the CANVAS findings. “We should give this warning that comparisons between trials are complicated by differences in populations, trial designs, analytic processes and drug effect, and the comparisons are hazardous and are subject to bias and may be confounded by multiple uncontrolled factors. Still ... if we look here at the [major adverse cardiac event] outcome — [CV] death, nonfatal MI or nonfatal stroke — you can see that the outcome here [in CANVAS] is almost identical to the EMPA-REG Outcome [result].”

Matthews said patients with type 2 diabetes and high CV risk would see the most benefit from initiating SGLT2 inhibitor therapy.

In an independent commentary after the presentation of the CANVAS program findings, Clifford J. Bailey, PhD, FRCP, FRCPath, professor of clinical sciences as Aston University in Birmingham, United Kingdom, said the patient populations in the two trials were different.

Clifford J. Bailey

“We can see here an important difference; namely, that EMPA-REG had 99% [of patients with] prior [CVD], whereas here [in CANVAS] we’re talking about 65% [of participants] with [CVD], which means that this is more reminiscent of the type of population you would see in routine practice.”

In EMPA-REG Outcome, Bailey said, there is an early and marked separation between the empagliflozin and placebo arms for the primary outcome, but, in CANVAS, the separation between canagliflozin and placebo was much more gradual.

“So, why might this be?” Bailey said. “Does it have something to do with the fact that EMPA-REG was looking at patients who nearly all had prior [CV] events? Or does it mean that you get a slower effect if you are dealing with more of a primary prevention situation? Could it possibly be agent-specific differences, or, in fact, might [the difference in results] have to do with differences in the placebo arm? Because this is the point at which the so-called placebo arm had the other components of treatment added in, so that’s a possibility.”

EMPA-REG researchers also recently reported additional stroke events in the study, Bailey said, attributed to events occurring more than 90 days after the last intake of empagliflozin.

“If that [stroke outcome] was recalculated without those data in, it would have been an HR of 1.08,” Bailey said. “The CANVAS study, we can see clearly here, has a gentle reduction in stroke all the way through, so there is an important difference there.”

In addition, new data from the CVD-REAL study also suggest that treatment with an SGLT2 inhibitor was associated with lower rates of death and heart failure compared with other glucose-lowering drugs, regardless of the presence or absence of CVD and the specific SGLT2 inhibitor used.

With CVD-REAL, “we can see, with patients starting on an SGLT2 inhibitor compared with other oral agents, a clear reduction ... in [heart failure] and all-cause mortality in all of these countries, the same sort of observation,” Bailey said. “If we look on the two sides of the Atlantic, between the U.S. and Europe, the same effect is seen with canagliflozin in the U.S. and the same effect in Europe with dapagliflozin. So, this would suggest that at least with heart failure and death, the benefits probably have something to do with a class effect.”

Amputation risk

Serious adverse events were less common in the canagliflozin group vs. placebo (104.3 events per 1,000 patient-years vs. 120 events per 1,000 patient-years); there were no between-group differences for adverse events leading to discontinuation. Researchers observed a higher risk for amputation of the toes, feet and legs in the canagliflozin group vs. placebo, with 6.3 participants with an amputation per 1,000 patient-years vs. 3.4 participants per 1,000 person-years; 71% of affected participants experienced their highest amputation at the toe or metatarsal, according to the researchers.

 

“The highest absolute risk for amputation occurred among patients who had a history of peripheral vascular disease, but the relative risk of amputation with canagliflozin as compared with placebo was similar across subgroups,” the researchers wrote in their report, published simultaneously online in The New England Journal of Medicine.

In the press conference, Neal said clinicians use caution when prescribing canagliflozin to patients at increased risk for an amputation, and further work is needed in this area. However, the CANVAS program met its primary objective of demonstrating CV safety while showing efficacy for the prevention of CV events.

“These data suggest a net overall benefit with canagliflozin for most patients with type 2 diabetes and high [CV] risk,” Neal said. – by Regina Schaffer

Disclosures: Janssen Research and Development sponsored this study. Matthews reports receiving research support, consultant or lecture fees from Ache Laboratories, Eli Lilly, GlaxoSmithKline, Janssen, Novartis, Novo Nordisk, Sanofi-Aventis and Servier. Please see the full study for the researchers’ relevant financial disclosures.

Patients with type 2 diabetes at high risk for cardiovascular disease assigned the SGLT2 inhibitor canagliflozin showed a 33% reduction in risk for hospitalization for heart failure and were 40% less likely to experience renal decline vs. those assigned placebo, according to findings from the integrated CANVAS study presented at the American Diabetes Association Scientific Sessions.

In a randomized, double blind, placebo-controlled trial conducted across 30 countries, researchers also noted that participants assigned canagliflozin (Invokana, Janssen) were twice as likely to experience an amputation, primarily at the toe or metatarsal, compared with those receiving placebo.

“The key question is: How do the risks and the benefits balance up?” Bruce Neal, MB, ChB, PhD, scientific director at The George Institute for Global Health, said during a press conference announcing the findings. “For 1,000 individuals treated [with canagliflozin] for 5 years ... there would be 23 fewer deaths from vascular disease, 17 fewer hospitalizations for heart failure and 16 fewer serious declines in renal function. By contrast, there would be 15 more amputations, and 10 of these would be at the toe or forefoot and five [would be] above the ankle.”

Study design, results

For the integrated CANVAS program, Neal and colleagues analyzed data from two trials involving 10,142 participants with type 2 diabetes and high CV risk, CANVAS (n = 4,330) and CANVAS-R (n = 5,812). The mean age for both trials was 63 years; 35.8% were women; mean duration of diabetes was 13.5 years; mean HbA1c, 8.2%; mean estimated glomerular filtration rate was 76.5 mL/min/1.73 m²; median urinary albumin to creatinine ratio was 12.3. Researchers randomly assigned participants in CANVAS to 100 mg or 300 mg canagliflozin or placebo; participants in CANVAS-R received an initial dose of 100 mg canagliflozin daily with an optional increase to 300 mg at week 13, or matching placebo. Follow-up occurred every 3 months for the first year and at 6-month intervals thereafter, with follow-up by telephone between in-person appointments. Serum creatinine and eGFR rate were measured at least every 26 weeks in both trials; urinary albumin to creatinine ratio was assessed every 26 weeks in CANVAS-R and at week 12 and annually in CANVAS. Primary outcome was a composite of death from CVD, nonfatal myocardial infarction and nonfatal stroke. Final follow-up occurred in February.

Within the cohort, 9,734 participants completed the trials; mean follow-up for both trials was 188.2 weeks, with a longer follow-up period in the CANVAS study (mean, 295.9 weeks). At baseline, 65.6% of participants had a history of CVD, 22.6% had microalbuminuria and 7.6% had macroalbuminuria.

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Researchers found that the rate of primary outcome was lower in participants assigned canagliflozin vs. placebo, occurring in 26.9 per 1,000 patient-years vs. 31.5 per 1,000 patient-years (HR = 0.86; 95% CI, 0.75-0.97).

Researchers also observed a possible benefit with respect to progression to albuminuria in the canagliflozin group (HR = 0.73; 95% CI, 0.67-0.79), as well as the composite outcome of a sustained 40% reduction in GFR, need for renal replacement therapy or renal death (HR = 0.6; 95% CI, 0.47-0.77).

Possible class effect

David R. Matthews

The findings from the integrated CANVAS study echo those from another study involving an SGLT2 inhibitor that initially surprised investigators. In the EMPA-REG Outcome trial, a randomized, double blind, placebo-controlled trial in 42 countries, researchers found that empagliflozin (Jardiance, Boehringer Ingelheim), when combined with standard care, reduced the risk for CV death by 38% compared with placebo in patients with type 2 diabetes with established vascular disease, with no significant difference in the risk for nonfatal MI or stroke. Patients treated with empagliflozin also experienced a 32% reduction in all-cause mortality risk and a 35% reduction in risk for hospitalization for heart failure, according to researchers. Within the EMPA-REG cohort (n = 7,020), 76% of participants had an established history of coronary artery disease; 46% of participants had a history of MI; between 9.5% and 10.5% of participants had a history of cardiac failure.

The EMPA-REG Outcome results, presented in September 2015, surprised researchers, who predicted CV-neutral results going into the study.

“There is obviously interest in interpreting [CANVAS] data in the context of the EMPA-REG Outcome [trial],” David R. Matthews, DPhil, FRCP, professor of diabetic medicine at the University of Oxford, said during a symposium discussing the CANVAS findings. “We should give this warning that comparisons between trials are complicated by differences in populations, trial designs, analytic processes and drug effect, and the comparisons are hazardous and are subject to bias and may be confounded by multiple uncontrolled factors. Still ... if we look here at the [major adverse cardiac event] outcome — [CV] death, nonfatal MI or nonfatal stroke — you can see that the outcome here [in CANVAS] is almost identical to the EMPA-REG Outcome [result].”

Matthews said patients with type 2 diabetes and high CV risk would see the most benefit from initiating SGLT2 inhibitor therapy.

In an independent commentary after the presentation of the CANVAS program findings, Clifford J. Bailey, PhD, FRCP, FRCPath, professor of clinical sciences as Aston University in Birmingham, United Kingdom, said the patient populations in the two trials were different.

PAGE BREAK
Clifford J. Bailey

“We can see here an important difference; namely, that EMPA-REG had 99% [of patients with] prior [CVD], whereas here [in CANVAS] we’re talking about 65% [of participants] with [CVD], which means that this is more reminiscent of the type of population you would see in routine practice.”

In EMPA-REG Outcome, Bailey said, there is an early and marked separation between the empagliflozin and placebo arms for the primary outcome, but, in CANVAS, the separation between canagliflozin and placebo was much more gradual.

“So, why might this be?” Bailey said. “Does it have something to do with the fact that EMPA-REG was looking at patients who nearly all had prior [CV] events? Or does it mean that you get a slower effect if you are dealing with more of a primary prevention situation? Could it possibly be agent-specific differences, or, in fact, might [the difference in results] have to do with differences in the placebo arm? Because this is the point at which the so-called placebo arm had the other components of treatment added in, so that’s a possibility.”

EMPA-REG researchers also recently reported additional stroke events in the study, Bailey said, attributed to events occurring more than 90 days after the last intake of empagliflozin.

“If that [stroke outcome] was recalculated without those data in, it would have been an HR of 1.08,” Bailey said. “The CANVAS study, we can see clearly here, has a gentle reduction in stroke all the way through, so there is an important difference there.”

In addition, new data from the CVD-REAL study also suggest that treatment with an SGLT2 inhibitor was associated with lower rates of death and heart failure compared with other glucose-lowering drugs, regardless of the presence or absence of CVD and the specific SGLT2 inhibitor used.

With CVD-REAL, “we can see, with patients starting on an SGLT2 inhibitor compared with other oral agents, a clear reduction ... in [heart failure] and all-cause mortality in all of these countries, the same sort of observation,” Bailey said. “If we look on the two sides of the Atlantic, between the U.S. and Europe, the same effect is seen with canagliflozin in the U.S. and the same effect in Europe with dapagliflozin. So, this would suggest that at least with heart failure and death, the benefits probably have something to do with a class effect.”

Amputation risk

Serious adverse events were less common in the canagliflozin group vs. placebo (104.3 events per 1,000 patient-years vs. 120 events per 1,000 patient-years); there were no between-group differences for adverse events leading to discontinuation. Researchers observed a higher risk for amputation of the toes, feet and legs in the canagliflozin group vs. placebo, with 6.3 participants with an amputation per 1,000 patient-years vs. 3.4 participants per 1,000 person-years; 71% of affected participants experienced their highest amputation at the toe or metatarsal, according to the researchers.

PAGE BREAK

 

“The highest absolute risk for amputation occurred among patients who had a history of peripheral vascular disease, but the relative risk of amputation with canagliflozin as compared with placebo was similar across subgroups,” the researchers wrote in their report, published simultaneously online in The New England Journal of Medicine.

In the press conference, Neal said clinicians use caution when prescribing canagliflozin to patients at increased risk for an amputation, and further work is needed in this area. However, the CANVAS program met its primary objective of demonstrating CV safety while showing efficacy for the prevention of CV events.

“These data suggest a net overall benefit with canagliflozin for most patients with type 2 diabetes and high [CV] risk,” Neal said. – by Regina Schaffer

Disclosures: Janssen Research and Development sponsored this study. Matthews reports receiving research support, consultant or lecture fees from Ache Laboratories, Eli Lilly, GlaxoSmithKline, Janssen, Novartis, Novo Nordisk, Sanofi-Aventis and Servier. Please see the full study for the researchers’ relevant financial disclosures.

    Perspective
    Alan J. Garber

    Alan J. Garber

    The results of CANVAS largely mirror those of EMPA-REG Outcome, thereby reinforcing the benefits of this relatively new class of antidiabetic agents. Since the mechanism or mechanisms by which such benefits are produced remain unclear, it is reassuring to have replication of these effects with another member of the class. On the other hand, CANVAS was associated with increased adverse effects in terms of fractures and, surprisingly, amputations, neither of which was found in EMPA-REG Outcome. This may influence drug selection in individual patients based upon their personal risk profiles, but should not affect class selection. The potential for cardiovascular benefit, together with hypoglycemia risk and weight change potential, will become the major second-level determinants of individual drug selection algorithms and prescriptions.

    • Alan J. Garber, MD, PhD, FACE
    • Chief Medical Editor, Endocrine Today

    Disclosures: Disclosure: Garber reports consulting for Intarcia and Novo Nordisk.

    Perspective
    George Bakris

    George Bakris

    The CANVAS program is really two studies in one; the results showed noninferiority for a 3-point major cardiac events endpoint as well as superiority over placebo. However, the CV death component of the primary outcome was not significant, nor was the MI or stroke component. All-cause mortality was reduced by 13%, but just missed significance. Like EMPA-REG Outcome, CANVAS showed a significant reduction in heart failure hospitalizations and reduced CV death from heart failure. Also like EMPA-REG Outcome, CANVAS showed a slowed progression of chronic kidney disease and albuminuria reduction.

    Unfortunately, there was a significant increase in amputations and a trend toward increased fracture risk in those assigned canagliflozin. In short, taken together with the EMPA-REG Outcome results, CANVAS findings support a role for SGLT2 inhibitors to reduce heart failure death and hospitalizations and reduce major cardiac events, as well as slow CKD progression, a secondary endpoint. In contrast, increased amputation rates and a trend toward a higher fracture rate was seen.

    • George Bakris, MD
    • Professor of Medicine Director ASH Comprehensive Hypertension Center University of Chicago Medicine

    Disclosures: Disclosure: Bakris reports consulting for AbbVie, Bayer, Janssen, Merck and Relypsa.