European Society of Cardiology

European Society of Cardiology

August 25, 2018
3 min read

SGLT2 inhibitor therapies may raise risk for amputation, diabetic ketoacidosis in diabetes with CVD

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MUNICH — Adults with type 2 diabetes and established CVD prescribed SGLT2 inhibitor therapy have a twofold increased risk for lower-limb amputation and diabetic ketoacidosis compared with patients prescribed a GLP-1 receptor agonist, according to study findings presented at the European Society of Cardiology Congress.

“Sodium glucose cotransporter 2 inhibitors are playing an increasingly prominent role in the treatment of diabetes, following the reduced risk of major adverse cardiovascular events and heart failure outcomes seen in the EMPA-REG Outcome trial with empagliflozin [Jardiance, Boehringer Ingelheim] and in the CANVAS study with canagliflozin [Invokana, Janssen],” Peter Ueda, MD, PhD, from the department of medicine at the Karolinska Institute in Solna, Sweden, said during a presentation here. “Concerns exist regarding the safety of the drugs, with signals of serious adverse events emerging from clinical trials, case reports and observational studies.”

In an observational study, Ueda and colleagues analyzed data from 17,213 patients without severe comorbidities who were prescribed any SGLT2 inhibitor, identified via nationwide registries in Sweden and Denmark. To reduce the risk for confounding by indication, Ueda said, researchers employed an active-comparator design with GLP-1 receptor agonist therapies, due to important shared features between the two drug classes in reducing CV risk and no known association for GLP-1 receptor agonists with the studied outcomes.

In both arms, the mean age was 61 years, 61% of participants were men, 19% had a history of CVD and 80% of patients were prescribed metformin therapy at baseline. Primary outcomes were one of seven serious adverse events: lower limb amputation, bone fracture, diabetic ketoacidosis, acute kidney injury, serious urinary tract infection, venous thromboembolism and acute pancreatitis. Researchers used Cox regression analysis for each outcome; median follow-up was 270 days.

Within the SGLT2 inhibitor arm, 61% of patients were prescribed dapagliflozin (Farxiga, Bristol-Myers Squibb/AstraZeneca), 38% of patients were prescribed empagliflozin and 1% of patients were prescribed canagliflozin.

Researchers observed a more than twofold increased risk for both lower-limb amputation and diabetic ketoacidosis for patients prescribed an SGLT2 inhibitor vs. a GLP-1 receptor agonist. For lower-limb amputation, the HR was 2.32 (95% CI, 1.37-3.91) for SGLT2 vs. GLP-1 receptor agonist use, with the largest absolute risk increases observed for those with a history of peripheral artery disease in the cohort (absolute risk difference, 14.9; 95% CI, 0.7-43.8), Ueda said.

For diabetic ketoacidosis, the HR for SGLT2 use was 2.14 vs. GLP-1 receptor agonist use (95% CI, 1.01-4.52), Ueda said.

Researchers found no significant increased risk for acute kidney injury, acute pancreatitis, bone fracture, serious urinary tract infection or venous thromboembolism associated with SGLT2 inhibitors.

Results persisted in sensitivity analyses adjusted for HbA1c, BMI, smoking status, albuminuria and estimated glomerular filtration rate. Ueda noted that that the study is observational and analyzed SGLT2 inhibitors as a drug class, and not individual agents.

“The use of SGLT2 inhibitors as compared to GLP-1 receptor agonists was associated with twofold increases for lower-limb amputation and diabetic ketoacidosis, but not with other serious adverse events of special concern,” Ueda said. “These findings should be interpreted in the context of limitations of observational studies, and these data are complementary to [randomized controlled trial] data.”

Ueda said the “uncertainty of estimates” should also be considered when reviewing the findings. For acute pancreatitis (HR = 1.16; 95% CI, 0.64-2.12), for example, the upper limit of the confidence interval was 2.12, whereas confidence intervals were consistent with a low to moderate relative increases in risk for the other four adverse outcomes analyzed, Ueda said.

In the OBSERVE-4D study presented at the American Diabetes Association Scientific Sessions in June and reported by, researchers found that adults with type 2 diabetes with and without established CVD treated with canagliflozin did not experience an increased risk for below-the-knee amputation compared with patients assigned similar SGLT2 inhibitors or other antidiabetes therapies. The real-world, retrospective analysis included more than 700,000 patients followed for a median of 6 months. In that study, researchers cautioned that physicians should consider factors that may increase risk for amputation when evaluating optimal therapies, such as history of prior amputation, peripheral vascular disease, neuropathy and diabetic foot ulcers. – by Regina Schaffer


Ueda P, et al. Late-Breaking Pharmacological Science. Presented at: European Society of Cardiology Congress; Aug. 25-29, 2018; Munich.

Disclosure: Ueda reports no relevant financial disclosures.