SGLT2 Inhibitor Amputation Risk Seen in Real-World Diabetes Study

Nancy A. Melville

November 14, 2018

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, increasingly used in the treatment of type 2 diabetes, show as much as a twofold increase in the risks of lower limb amputations and diabetic ketoacidosis compared with glucagon-like peptide 1 (GLP-1) receptor agonists in a large real-world study of Swedish and Danish patients.

But the risks are still relatively small and should be weighed in relation to the drugs' benefits, the authors underscore.

"Our study adds to the data on the safety of these drugs by assessing the association between SGLT2 inhibitor use and serious adverse events in a substantially different population as compared to those included in the clinical trials — a population representative of routine clinical practice," first author Peter Ueda, PhD, of the Clinical Epidemiology Division, Department of Medicine, Karolinska Institute, Stockholm, Sweden, told Medscape Medical News.

However, "it is important to emphasize that the absolute risk increases observed for diabetic ketoacidosis and lower limb amputation in our study were small," he added. "The potential risk of adverse events should be considered in the context of the benefits of SGLT2 inhibitors, including the beneficial effects on cardiovascular and renal outcomes."

Use of Canagliflozin Rare in This Study Population

To evaluate the drugs' safety outside of clinical trials in a larger population of patients from routine clinical practice, Ueda and colleagues turned to nationwide registry data on new users of SGLT2 inhibitors in Sweden and Denmark between July 2013 and December 2016.

The study, published online November 14 in BMJ, included 17,213 patients taking SGLT2 inhibitors (61%, dapagliflozin [Farxiga, Xigduo XR, AstraZeneca]; 38%, empagliflozin [Jardiance, Lilly/Boehringer Ingelheim]; and 1%, canagliflozin [Invokana, Janssen]), who were matched with 17,213 new users of the active comparator, GLP-1 receptor agonists.

The patients, who were aged 35 years and older, had no history of severe kidney problems or pancreatic disorders.

With a median follow-up of 270 to 274 days, and after adjusting for factors ranging from disease history to other medication use and sociodemographic parameters, SGLT2 inhibitor use showed a significantly greater incidence rate of lower limb amputation compared with GLP-1 receptor agonist use (incidence rate 2.7 vs 1.1 events per 1000 person-years; hazard ratio [HR], 2.32).

SGLT2 inhibitor use was also linked to an increased risk of diabetic ketoacidosis (1.3 vs 0.6; HR, 2.14).

But there was not a significant increase in the other primary outcomes, including bone fracture (15.4 vs 13.9; HR, 1.11), acute kidney injury (2.3 vs 3.2; HR, 0.69), serious urinary tract infection (5.4 vs 6.0; HR, 0.89), venous thromboembolism (4.2 vs 4.1; HR, 0.99), or acute pancreatitis (1.3 vs 1.2; HR, 1.16).

The results were consistent regardless of whether or not patients had cardiovascular disease, peripheral arterial disease, or previous amputation.

However, the authors note that the event rates were substantially higher among groups who did have those histories.

Results Are Consistent With Previous, But Not All, Findings

Ueda and colleagues say their findings regarding lower limb amputation — primarily at the level of the toe or metatarsal — are consistent with those observed with canagliflozin in the CANVAS trial program (N Engl J Med. 2017;377:644-657), as reported by Medscape Medical News.

The US Food and Drug Administration (FDA) issued a safety alert for canagliflozin in 2016 relating to amputation concerns following an interim report from the CANVAS trial program.

In addition, concerns about amputation risk with SGLT2 inhibitors have prompted a call by the European Medicines Agency for a warning of the risk on labels for all drugs in this class in the European Union, as reported by Medscape Medical News. European authorities felt they could not be sure that the risk of amputation was not a class effect.

Indeed, Ueda and colleagues stress that the use of canagliflozin was rare in their population, which was taken by only 1% of patients.

The CANVAS program also showed an increased risk of bone fracture in people taking canagliflozin, but other trials of the drug have not replicated this finding, similar to the current study.

The twofold increase in diabetic ketoacidosis seen in the current study is consistent with a recent analysis of insurance claims in the US that compared SGLT2 inhibitors with DPP4 inhibitors (N Engl J Med. 2017;376:2300-2302).

And various other studies have also linked diabetic ketoacidosis to SGLT2 inhibitors.

"Viewed together, a relatively coherent picture of an increased risk of diabetic ketoacidosis associated with the use of SGLT2 inhibitors has emerged, although the absolute risk increase seems small," say Ueda and coauthors.

The FDA has also warned about the risk of diabetic ketoacidosis associated with SGLT2 inhibitors.

In limiting the study to new users with no history of use of either study drug at cohort entry, the authors sought to limit the risk of confounding. And in a sensitivity analysis of the Swedish cohort, representing 61% of the entire population, adjustments were also made for factors including HbA1c level, blood pressure, albuminuria, estimated glomerular filtration rate, body mass index, and smoking status.

"The consistency of results between these analyses and our main analyses indicate that confounding owing to these variables was minimal, although some of these analyses had few events for each variable used for multivariate adjustment."

Footcare Recommendations Important When Prescribing SGLT2 Inhibitors

In terms of counseling patients about the risks and benefits, Ueda recommends making awareness of footcare a priority when prescribing SGLT2 inhibitors.

"Our findings should lead to further emphasis on the importance of counseling patients on routine preventative footcare," he stressed.

"Moreover, patients at high risk of amputation, for example those with peripheral artery disease or foot ulcers, might be monitored more closely if an SGLT2 inhibitor, in particular canagliflozin, is used, and the patient's risk of this adverse event may be considered when deciding which drugs to use."

The study received support from the Swedish Heart-Lung Foundation, Swedish Cancer Society, Nordic Cancer Union, Novo Nordisk Foundation, and Swedish Society for Medical Research.

BMJ. Published November 14, 2018. Abstract

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