Canagliflozin Use in Patients With PAD Linked to Reduced Risk for CV, Renal Outcomes

CT angiography of PAD, peripheral artery disease
Investigators examined the effect of canagliflozin in patients with both type 2 diabetes and peripheral artery disease.

Treatment with the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin has been shown to consistently decrease the proportional risks for cardiovascular (CV) and renal outcomes regardless of peripheral artery disease (PAD) status at baseline, with no relative increase in the total number of adverse events  or major adverse limb events in individuals with or without PAD. These findings were published in the journal Diabetes, Obesity and Metabolism.

A post hoc subgroup analysis of pooled individual participant data from the CANVAS Program ( identifier: NCT01032629) and the CREDENCE trial ( identifier: NCT02065791) was conducted. The researchers of the analysis sought to define the proportional and absolute benefits of canagliflozin in patients with type 2 diabetes (T2D) with or without PAD. The primary outcome for the CANVAS Program was major adverse limb events (MALE). For the CREDENCE trial, the primary outcome was a composite of renal failure (ie, dialysis for ≥30 days, kidney transplantation, or estimated glomerular filtration rate [eGFR] of less than 15 mL/min/1.73 m2), doubling of serum creatinine, or death due to renal or CV disease. In this post hoc analysis, the main outcomes of interest included major adverse cardiovascular events (MACE), renal outcomes, and extended MALE.

A total of 14,543 patients were enrolled in both studies. A total of 10,142 patients enrolled in the CANVAS Program and 4401 in the CREDENCE trial. Of these patients, 3159 had PAD at baseline. Individuals with PAD in the CANVAS Program and the CREDENCE trial were older, more likely to be White, have a longer duration of T2D, and have cerebrovascular disease, microvascular disease, history of amputation, and a heart failure (P <.0001 for all).

Participants with PAD also exhibited poorer CV risk factor control (which included low-density lipoprotein cholesterol, systolic blood pressure, and hemoglobin A1c), as well as a significantly lower eGFR (P =.0001) and a significantly higher urine albumin/ creatinine ratio (P <.0001). Further, individuals with PAD exhibited increased odds of insulin, antithrombotic, and diuretic medication use (P <.0001 for all).

Among the 3159 patients with PAD at baseline, canagliflozin reduced MACE (hazard ratio [HR], 0.76; 95% CI, 0.62-0.92). For every 1000 individuals treated with canagliflozin over 2.5 years, the agent prevented approximately 33 MACE in patients with PAD (95% CI, -56 to -9) compared with 11 MACE in those without PAD (95% CI, -20 to -2).

Similar relative benefits for other CV and kidney outcomes were reported in participants with and without PAD at baseline (Pinteraction >.268 for all). Further, no increase in the relative risk for extended MALE was reported with canagliflozin treatment, regardless of baseline PAD history (Pinteraction >.864).

Canagliflozin was associated with a decrease in total serious adverse events (AEs) in those with PAD at baseline (HR, 0.85; 95% CI, 0.76-0.95). In absolute terms, 79 fewer serious AEs were reported per 1000 patients treated with canagliflozin over 2.5 years in those with PAD (95% CI, -136 to -19) compared with 30 fewer serious AEs in those without a history of PAD (95% CI, -54 to -7).

Although the current post hoc analysis benefits from the rigorous design and conduct of the contributing studies, a large population (>3000 participants) with PAD at study entry, and a long follow-period, “it was not . . . powered to detect differences in those with and without PAD, and small or moderate sized differences in effects between subgroups may have been missed.” Thus, the findings should be interpreted with caution.

The researchers concluded that although the study findings show that patients with T2D and PAD derive similar relative cardiorenal benefits from canagliflozin treatment, the absolute benefits are greater among those with PAD compared with those without PAD.

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Barraclough JY, Yu J, Figtree GA, et al. Cardiovascular and renal outcomes with canagliflozin in patients with peripheral arterial disease: data from the CANVAS Program and CREDENCE trial. Diabetes Obes Metab. Published online February 15, 2022. doi:10.1111/dom.14671