CANVAS

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Neal B, et al. "Canagliflozin and cardiovascular and renal events in type 2 diabetes". The New England Journal of Medicine. 2017. 377(7):644-657.
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Clinical Question

Among patients with T2DM at high risk for CV events, does daily canagliflozin reduce CV mortality, nonfatal MI, or nonfatal strokes when compared to placebo?

Bottom Line

Among patients with T2DM at high risk for CV events, canagliflozin had a lower risk of cardiovascular events and reduced the rate of renal decline and heart failure hospitalization compared to those who received placebo but a greater risk of amputation.

Major Points

Mortality in T2DM is mainly related to an increased incidence of CV disease.[1] While standard medications such as insulin, sulphonylureas, and DPP4 inhibitors all effectively reduce blood glucose, these agents have not been associated with improvements in a cardiovascular disease or survival. The thiazolidinedione pioglitazone in PROactive (2005) and the DDP4 inhibitors alogliptin in EXAMINE (2013) and saxagliptin in SAVOR-TIMI 53 (2013)[2] and TECOS (2015)[3] have all failed to demonstrate cardiovascular benefits or improved survival in this patient population.

The multicenter Canagliflozin Cardiovascular Assessment Study (CANVAS) program is comprised of data from two sister trials involving a total of 10,142 patients with T2DM at high risk of CV complications. The CANVAS patients were randomized 1:1:1 to canagliflozin 100 mg/d or 300 mg/d or placebo, and the CANVAS-R patients were randomized to receive canagliflozin at an initial dose of 100 mg/d with an option to increase to 300 mg/d at week 13 or matching placebo. At mean follow-up of 188 weeks, canagliflozin was associated with a reduction in death from CV causes, nonfatal MI, or nonfatal stroke (26.9 vs. 31.5 per 1,000 patient-years; HR 0.86; 95% CI 0.75-0.97) with a possible benefit with respect to the progression of albuminuria (HR 0.73; 95% CI 0.67-0.79), the composite outcome of reduction in GFR, need for renal-replacement therapy or death from renal causes (HR 0.60; 95% CI 0.47-0.77), and hospitalization for heart failure (HR 0.67; 95% CI, 0.52-0.87). As with empagliflozin, there was a greater incidence of genital infections. However, canagliflozin was associated with a significant doubling in the risk of amputations (6.3 vs. 3.4 per 1000 patient-years; HR 1.97; 95% CI, 1.41 to 2.75), primarily of the toe or metatarsal.

Interestingly, the HbA1c reduction with empagliflozin and canagliflozin was modest at best (0.5% and 0.58%, respectively). Given that multiple previous clinical trials (ACCORD 2008, ADVANCE 2008, VADT 2009) did not demonstrate a reduction in major adverse CV events with intensive glucose-lowering therapy, it remains unclear what mechanisms drive the CV benefits seen with empagliflozin and canagliflozin.

Guidelines

As of August 2017, no guidelines have been published that reflect the results of this trial.

Design

  • Two multicenter, randomized, double-blind, placebo-controlled trial
  • N=10,142 (4330 in CANVAS and 5812 in CANVAS-R; 96% completed trial)
    • Canagliflozin 100mg vs. 300mg daily vs. Placebo
    • Canagliflozin 100mg then 300mg daily vs. Placebo
  • Setting: 667 centers in 30 countries involved in two trials
  • Enrollment: 2009-2013
  • Median follow-up: 126 weeks; mean follow-up: 188 weeks
  • Analysis: Intention-to-treat
  • Primary outcome: CV mortality, nonfatal MI, or nonfatal stroke

Population

Inclusion Criteria

  • T2DM with HbA1c ≥7.0% to ≤10.5% at screening
  • Not currently on antihyperglycemic agent therapy or on antihyperglycemic monotherapy or combination therapy with approved class of agents: e.g., sulfonylurea, metformin, PPAR-gamma agonist, alpha-glucosidase inhibitor, GLP-1 analog, DPP-4 inhibitor, or insulin
  • History or high risk of CV disease defined on basis of either:
    • Age ≥30 yrs with documented symptomatic atherosclerotic CV disease: including stroke; MI; hospitalization for UA; CABG; PCI; peripheral revascularization; symptomatic with documented hemodynamically-significant carotid or peripheral vascular disease; or amputation secondary to vascular disease.
    • Age ≥ years with 2+ following risk factors at screening: duration of T2DM ≥10 years, SBP>140 mmHg, while on ≥1 BP-lowering Tx, current daily cigarette smoker, documented microalbuminuria or macroalbuminuria, or documented HDL <1mmol/l(<39 mg/dl)
  • Women must be:
    • Postmenopausal, defined as >45 years with amenorrhea ≥18 mos, or >45 years with amenorrhea ≥6 mos and less than 18 mos and FSH>40 IU/ml, or
    • Surgically sterile (have had hysterectomy or bilateral oophorectomy, tubal ligation) or incapable of pregnancy
    • Heterosexually active and practicing highly effective method of birth control
    • Not hetero-sexually active
  • Women of childbearing potential must have negative urine beta-HCG pregnancy test at screening

Exclusion Criteria

  • History of DKA, type 1 DM, pancreas or beta-cell transplantation, or diabetes secondary to pancreatitis or pancreatectomy
  • On antihyperglycemic agent and not on stable regimen for at least 8 weeks
  • Fasting FS glucose >270 mg/dl (>15 mmol/l) on Day 1
  • Fasting FS glucose at site <110 mg/dl (<6 mmol/l) at baseline for pts on sulfonylurea agent or on insulin
  • History of ≥1 severe hypoglycemic episode within 6 mos screening
  • History of hereditary glucose-galactose malabsorption or primary renal glucosuria
  • Ongoing, inadequately controlled thyroid disorder
  • Renal disease requiring treatment with immunosuppressive therapy or history of dialysis or renal transplant
  • MI, UA, revascularization, or CVA within 3 mos screen, or planned revascularization procedure or history of NYHA Class IV cardiac disease
  • Findings on 12-lead ECG that would require urgent diagnostic evaluation or intervention
  • History of positive HBSAg or HCV Ab, or other clinically active liver diseases
  • History of or planned bariatric surgery
  • GFR <30 at screening
  • Serum Cr ≥1.4 mg/dL for men or ≥1.3 for women for those taking metformin
  • ALT >2.0x ULN or total bilirubin >1.5x ULN at screening
  • History of malignancy within 5 years
  • History of HIV Ab positive
  • Current clinically important hematological disorder
  • Life expectancy <1 year
  • Major surgery within 3 mos or any surgery planned during participation in study
  • Current use of other SGLT2 inhibitor
  • Known allergies, hypersensitivity, intolerance to canagliflozin
  • Current or expected use of corticosteroid medication or immunosuppressive agent
  • History of drug or ETOH abuse within 3 years
  • Pregnant or breastfeeding

Baseline Characteristics

  • Age 63 years, female sex 36%
  • White 78%, Asian 13%, Black 3%
  • Current smoker 18%
  • History of hypertension 90%
  • History of HF 14%
  • Duration of DM 13.5 years
  • History of microvascular disease
    • Retinopathy 21%
    • Nephropathy 18%
    • Neuropathy 31%
  • History of atherosclerotic vascular disease
    • Coronary 56%
    • Cerebrovascular 19%
    • Peripheral 21%
    • Any 72%
  • History CV disease 66%
  • History of amputation: 2%
  • BMI 32 kg/m2, BP 137/78 mmHg
  • Laboratory: HbA1c: 8.2%; Tchol 4.4 mmol/L, HDL 1.2 mmol/L, LDL 2.3 mmol/L, TG 2.0 mmol/L; GFR 76
  • Median albumin-to-creatinine ratio 12.3; normoalbuminuria 70%; microalbuminuria 23%; macroalbuminuria 8%

Interventions

  • Participants in CANVAS randomized in a 1:1:1 ratio:
    • Canagliflozin 300 mg
    • Canagliflozin 100 mg
    • Placebo
  • Participants in CANVAS-R randomized in 1:1 ratio:
    • Canagliflozin at initial dose of 100 mg daily with optional increase to 300 mg at week 13
    • Placebo
  • All doses were taken daily after a 2 week single-blind, placebo run-in period
  • Face-to-face follow-up scheduled in 3 visits during first year and at 6-mo intervals thereafter, with telephone follow-up between face-to-face assessments
    • Every follow-up included inquiry about primary and secondary outcome events and serious adverse events
    • Urinary albumin-to-creatinine ratio measured every 26 wks in CANVAS-R and at week 12 and then annually in CANVAS
    • Serum Cr with eGFR measured every 26 weeks
  • Total of 71.4% CANVAS-R had dose of canagliflozin increased to 300 mg during trial

Outcomes

Comparisons are canagliflozin vs. placebo. P-values are for superiority except where specified.

Primary Outcomes

CV mortality, nonfatal MI, or nonfatal stroke
26.9 vs. 31.5 participants with an event per 1000 patient-years (HR 0.86; 95% CI, 0.75 to 0.97; P<0.001 for noninferiority; P=0.02 for superiority)

Secondary Outcomes

All-cause mortality
17.3 vs. 19.5 participants with an event per 1000 patient-years (HR 0.87; 95% CI 0.74 to 1.01; NS)
CV mortality
11.6 vs. 12.8 participants with an event per 1000 patient-years (HR 0.87; 95% CI 0.72 to 1.06; NS)
Progression of albuminuria (>30% increase in albuminuria)
89.4 vs. 128.7 participants with event per 1000 patient-years (HR 0.73; 95% CI, 0.67 to 0.79)
40% reduction in eGFR, renal-replacement therapy or renal death
5.5 vs. 9.0 participants with event per 1000 patient-years (HR 0.60; 95% CI, 0.47 to 0.77)
Hospitalization for any cause
118.7 vs. 131.1 participants with event per 1000 patient-years (HR 0.94; 95% CI, 0.88 to 1.00)
Hospitalization for heart failure
5.5 vs. 8.7 participants with event per 1000 patient-years (HR 0.67; 95% CI, 0.52 to 0.87)
CV mortality and hospitalization for heart failure
16.3 vs. 20.8 participants with event per 1000 patient-years (HR 0.78; 95% CI, 0.67 to 0.91)

A full list of secondary outcomes are presented in Figure 3 of the main text. Outcomes that did not reach statistical significance for differences between groups include nonfatal MI, nonfatal stroke, fatal or nonfatal MI, fatal or nonfatal stroke.

Additional Outcomes

Comparisons are canagliflozin vs. placebo.

Mean difference in A1c
-0.58% (95% CI -0.61 to -0.56) (P<0.001)
Mean difference in body weight
-1.60 kg (95% CI, -1.70 to -1.51) (P<0.001)
Mean difference in SBP
-3.93 mmHg (95% CI, -4.30 to -3.56) (P<0.001)
Mean difference in DBP
-1.39 mmHg (95% CI, -1.61 to -1.17) (P<0.001)
Use of other antihyperglycemic agents during follow-up
9.3% lower (95% CI, -11.0 to -7.6)
HDL cholesterol
2.05 mg/dl higher (95% CI, 0.05-0.06)
LDL cholesterol
4.68 mg/dL (95% CI, 0.09 - 0.15)

Subgroup Analysis

For the primary outcome.

Favors canagliflozin
Age ≥65
BMI ≥30
Duration of diabetes ≥10 yrs
Glycated hemoglobin ≥8%
eGFR 30 to <60
History of cardiovascular disease
History of peripheral vascular disease
No history of amputation
Statin use
Beta-blocker use
Diuretic use

Adverse Events

All serious
104.3 vs. 120.0 participants with event per 1000 patient-years (HR 0.93; 95% CI, 0.87 to 1.00; P=0.04)
Events leading to discontinuation
35.5 vs. 32.8 participants with event per 1000 patient-years (P=0.07)
Risk of amputation of toes, feet or legs
6.3 vs. 3.4 participants per 1000 patient-years (HR 1.97; 95% CI, 1.41 to 2.75) with 71% affected participants having their highest amputation at level of toe or metatarsal
Infection of male genitalia
34.9 vs. 10.8 participants with event per 1000 patient-years (P<0.001)
Osmotic diuresis
34.5 vs. 13.3 participants with event per 1000 patient-years (P<0.001)
Volume depletion
36.0 vs. 18.5 participants with event per 1000 patient-years (P=0.009)
Mycotic genital infection in women
69 vs. 18 participants with event per 1000 patient-years (P<0.001)

Criticisms

  • Few ESRD events
  • Few patients with baseline CKD

Funding

  • Janssen, manufacturers of canagliflozin (Invokana) were the primary sources of funding for the study.

Further Reading

  1. Tancredi M, et al. "Excess mortality among persons with type 2 diabetes." The New England Journal of Medicine. 2015;373:1720-1732.
  2. White WB et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N. Engl. J. Med. 2013. 369:1327-35.
  3. Scirica BM et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N. Engl. J. Med. 2013. 369:1317-26.