Update on canagliflozin and risk of lower limb amputation

Canagliflozin (Invokana™, Johnson & Johnson Pte Ltd) is a member of a new class of antidiabetic agents known as sodium-glucose cotransporter-2 (SGLT2) inhibitors. It has been registered locally since February 2014 and is indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus (T2DM).

In May 2016, a Dear Healthcare Professional Letter (DHCPL) was issued by the company to inform healthcare professionals about an increased risk of lower limb amputation (LLA) with canagliflozin observed in an ongoing long-term cardiovascular outcome trial (CVOT), called the Canagliflozin Cardiovascular Assessment Study (CANVAS).¹ This article provides an update on the LLA-related safety findings from the integrated analysis of the completed trial and its sister study, as well as the international regulatory actions taken.

CANVAS program and LLA-related safety findings

The CANVAS program comprised two sister studies, CANVAS and CANVAS-Renal (CANVAS-R), which were similar in study design and subject eligibility criteria. The primary objective of the CANVAS study was to evaluate the cardiovascular (CV) risk of canagliflozin while the primary objective of the CANVAS-R study was to assess the effect of canagliflozin on the progression of albuminuria and diabetic nephropathy. The subject population enrolled in both studies was T2DM patients who had inadequate glycaemic control (HbA1c ≥7.0% and ≤10.5%) with either known CV disease or two or more risk factors for CV events. A total of 10,134 subjects were enrolled in these two studies, of which 65% had pre-existing CV disease. Subjects in CANVAS and CANVAS-R studies were followed for an average of 5.7 and 2.1 years, respectively.

Integrated analysis of these two studies was prespecified and aimed to assess the CV safety of canagliflozin, in fulfilment of the US Food and Drug Administration’s (FDA) post-marketing requirement.² The CANVAS and CANVAS-R studies were initiated in December 2009 and January 2014, respectively, and both studies were completed in February 2017.

Patients treated with canagliflozin had a lower risk of CV events than those who received placebo. However, an approximately two-fold increased risk of LLA (primarily of the toe and midfoot) was observed in patients treated with canagliflozin compared to placebo (Table 1). The imbalance in LLA incidence occurred as early as the first 26 weeks of therapy, and in a dose-independent manner.

Multiple amputations (some involving both lower limbs) were observed infrequently and in similar proportions in both treatment groups. Regardless of treatment with canagliflozin or placebo, the risk of amputation was highest in patients with a baseline history of prior amputation, peripheral vascular disease and neuropathy. Lower limb infections, diabetic foot ulcers, peripheral arterial disease and gangrene were the most common medical events associated with the need for an amputation in both treatment groups.

Table 1. Integrated analysis of amputation in the CANVAS program

	Placebo (n=4,344)	Canagliflozin (n=5,790)
Total number of subjects with events, n (%)	47 (1.1%)	140 (2.4%)
Incidence rate (per 100 subject-years)^[a]	0.34	0.63
Hazard ratio (95% confidence interval) versus placebo	-	1.97 (1.41, 2.75)
Minor amputation, n (%) ^[b]	34/47 (72.3%)	99/140 (70.7%)
Major amputation, n (%) ^[c]	13/47 (27.7%)	41/140 (29.3%)

^[a]Incidence was based on the number of patients with at least one amputation, and not the total number of amputation events. Some patients had more than one amputation

^[b]Toe and midfoot

^[c]Ankle, below knee and above knee

Risk of LLA with other SGLT2 inhibitors

To date, the evidence suggesting an increased risk of LLA with SGLT2 inhibitors other than canagliflozin is limited. The CVOT for empagliflozin, known as the EMPA-REG OUTCOME study, did not systematically capture the amputation events. A total of 7,020 T2DM patients with high CV risk, 99.5% of which had pre-existing CV disease, were enrolled in this study.³ Post-hoc analysis of LLA-related adverse events identified in this study found no difference in the risk of LLA between empagliflozin and placebo (HR 1.00 [95% CI 0.70, 1.44]).⁴

The CVOT of dapagliflozin, known as DECLARE-TIMI 58, is ongoing and expected to be completed in July 2018.⁵

International regulatory actions

(a) European Medicines Agency (EMA)

In April 2016, EMA initiated a safety review to evaluate the risk of LLA associated with canagliflozin, which was subsequently extended to the other SGLT2 inhibitors (i.e. dapagliflozin and empagliflozin). The safety review, completed in February 2017, concluded that canagliflozin might contribute to the risk of LLA although the mechanism of canagliflozin-induced LLA remained unclear. In addition, although the available data suggesting a class effect of SGLT2 inhibitors on LLA risk were limited, this risk might also apply to other SGLT2 inhibitors.⁶ As a result, the European package inserts (PIs) for all SGLT2 inhibitor-containing products were updated to warn about this risk. In contrast to the European PI for canagliflozin which carried specific warnings on canagliflozin and LLA, the updated LLA-related safety information in the European PIs of dapagliflozin- and empagliflozin-containing products provided a more general warning, highlighting the increased risk of LLA with another SGLT2 inhibitor and the unknown class effect of SGLT2 inhibitors on the risk of LLA.⁷

(b) US FDA

The US FDA also conducted a review on this safety issue and issued a safety communication in May 2017, highlighting its recommendation to strengthen the US PIs of canagliflozin-containing products with new warnings, including a boxed warning, on the increased risk of leg and foot amputations.⁸

Local situation and HSA’s advisory

To date, HSA has not received any local reports of LLA associated with canagliflozin or other SGLT2 inhibitors. Following the issuance of the DHCPL in May 2016, the local PI for Invokana™ was updated to warn about the risk of LLA, and is currently in the process of being updated to include findings from the integrated analysis of the CANVAS program.

Healthcare professionals are advised to take into consideration the above safety information when prescribing canagliflozin, and to monitor canagliflozin-treated patients for complications which may precede LLA, such as lower-extremity skin ulcer, infection, osteomyelitis or gangrene. They should also consider counselling their patients about the importance of routine preventive foot care and maintaining adequate hydration.

HSA will continue to closely monitor the local and international developments regarding the risk of LLA with SGLT2 inhibitors and will update healthcare professionals of any new significant findings. Healthcare professionals are encouraged to report any serious adverse reactions, including amputations, related to SGLT2 inhibitors to the Vigilance and Compliance Branch of HSA.

References

https://www-hsa-gov-sg.cwp.sg/announcements/dear-healthcare-professional-letter/risk-of-lower-limb-amputations-(primarily-of-the-toes)-during-treatment-with-invokana-(canagliflozin)

Diabetes Obes Metab. 2017;19:926-935.

Diabetes Ther. 2017;8:1245-1251.

Diabetes Care. 2018;41:e4-e5.

Healthcare professional, Industry member, Therapeutic Products

Published: 11 May 2018

Safety Alerts

12 Dec 2019