CANVAS Program: The Synergistic Impact of Canagliflozin with GLP1 RA on Intermediate Markers of CV Risk in T2DM

Background

Sodium glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP1-RA) not only improve intermediate markers of cardiometabolic health but also reduce the cardiovascular (CV) events , in patients with type-2 diabetes mellitus (T2DM). Considering the differential mechanism of action of both these classes of medication, a combination therapy may be beneficial in T2DM patients.

Aim

To determine the impact of canagliflozin on the clinical outcomes of patients who were receiving vs. not receiving GLP1-RA at baseline during the CANVAS Program.

Patient Profile

• Patients with T2DM [glycated hemoglobin (HbA1c) between ≥7% and ≤10.5%, age ≥ 30 years, n=10142)
• The study participants either had a history of symptomatic atherosclerotic CVD or were aged ≥50 years with ≥2 CV risk factors

Methods

Study Design

• Post hoc analysis of the CANVAS Program

• The CANVAS Program comprised of 2 double-blind, randomized, placebo-controlled trials (CANVAS and CANVAS-R)

Treatment Strategy

• Patients were randomized to receive canagliflozin or placebo along with other background antidiabetic medications.
• The use of GLP1-RA was self-reported by the study participants

Outcomes

Primary Outcome

• A composite of CV death, nonfatal myocardial infarction, or nonfatal stroke

Secondary Outcomes (Prespecified intermediate markers)

• HbA1c
• Systolic blood pressure (SBP)
• Body weight
• Urinary albumin:creatinine ratio (UACR)
• Estimated glomerular filtration rate (eGFR)

Results

• Of the 10142 study participants, 407 (4%) were using GLP1-RA at baseline (4% in canagliflozin and placebo group each).
• During the study, GLP1-RA was initiated in 138 and 148 participants from the canagliflozin and placebo group, respectively.
• Patients using GLP1-RA at baseline were less likely to have a history of CVD (60.4% vs. 65.8%), had a longer duration of diabetes (15.2 vs. 13.5 years) and a higher body mass index (BMI; 35.6 vs. 31.8 kg/m²) vs. those not receiving GLP1-RA. The other baseline characteristics did not differ significantly between the patients receiving GLP1-RA vs. those not receiving GLP1-RA.
• The incidence of primary CV outcomes, composite renal outcomes or total serious adverse events did not differ between those who received GLP1-RA and those who didn’t receive.
• Amongst patients receiving GLP1-RA vs. those not receiving GLP1-RA at baseline, treatment with canagliflozin vs. placebo was associated with greater reductions in HbA1c, SBP, and body weight (Table 1).

• Overall, the UACR (P=0.21), eGFR slope (P=0.72) and total serious adverse events (P = 0.74) decreased in canagliflozin vs. placebo group irrespective of GLP1-RA treatment

Conclusion

• Treatment with SGLT2 inhibitors may have a synergistic effect on intermediate cardiometabolic markers while retaining the beneficial cardio-renal effects in T2DM patients being treated with GLP1-RA.

 Int J Cardiol.   Jun 20, 2020 (Published Online); DOI: 10.1016/j.ijcard.2020.06.011.