SGLT2 Inhibitors and Amputations in Diabetes: Still Unclear

Miriam E. Tucker

August 15, 2018

Use of sodium-glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes may be associated with an increased risk for below-the-knee amputations compared with some oral diabetes therapies but not others, new research suggests.

Findings from the retrospective cohort study using real-world claims data were published online August 13 in JAMA Internal Medicine by Hsien-Yen Chang, PhD, of the Center for Drug Safety and Effectiveness, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, and colleagues.

Concern about amputations with SGLT2 inhibitors first arose in May 2016 when interim data from the Canagliflozin Cardiovascular Assessment Study (CANVAS) revealed a significant increase in amputation rates with the drug compared with placebo: 6.3 vs 3.4/1000 patient-years (hazard ratio, 1.97). Most were toe amputations.

The US Food and Drug Administration (FDA) then issued a drug safety communication warning about the risk of foot and lower leg amputation with canagliflozin (Invokana, Janssen)but not other SGLT2 inhibitors. In contrast, the label warning in Europe covers all drugs in the class, even though the same risk has not been seen with other SGLT2 inhibitors.

Since then, other data have not supported the association between canagliflozin and amputations, including another large observational study presented at the American Diabetes Association (ADA) 2018 Scientific Sessions in June 2018.  

CANVAS Data Remain Strongest Indicator of Amputation Risk

The new study by Chang and colleagues investigated more than 1 million new users of oral glucose-lowering medications using propensity score weighting and adjustments for confounders. Initiation of SGLT2 inhibitors was associated with a significantly greater risk for amputations compared with new use of sulfonylureas, metformin, and thiazolidinediones, and a nonsignificant increased risk compared with dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists.

"Given the uncertainty regarding the true nature of the association between SGLT2 inhibitors and amputation, clinicians and patients will have to navigate treatment choices while balancing the potential risks of these products against their benefits and alternatives," Chang and colleagues write.

In an accompanying editorial, Michael Fralick, MD, and colleagues, of the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, fault the study for what they deem as flawed statistical methodology, but essentially come to similar conclusions.

"The important question for patients and physicians is whether SGLT2 inhibitors are associated with an increased risk of amputation. The study by Chang et al helps to contextualize the risk in a relatively low-risk patient population, but does not settle the debate," Fralick and colleagues write.

Still unclear, they say, is "if the risk of amputation is a class effect for all SGLT2 inhibitors and how the risk observed in CANVAS will translate to older and sicker patients not included in the study by Chang et al."

"Until more data are available, the results of CANVAS provide the greatest evidence that canagliflozin is associated with an increased risk of amputation and should influence our prescribing accordingly."

Increased Risk Seen Against Some Other Oral Diabetes Drugs

Chang and colleagues used the Truven Health MarketScan Commercial Claims and Encounters database, which contains information on more than 25 million commercially insured individuals annually.

They derived two cohorts from 2.0 million new users of oral glucose-lowering medications between September 2012 and September 2015: one excluded individuals with baseline amputation (n = 953,906) and another excluded individuals with any baseline outcome (n = 933,073).

The first cohort included 39,869 new users of SGLT2 inhibitors (4.2%), 105,023 of DPP-4 inhibitors (11.0%), and 39,120 of GLP-1 agonists. Among the SGLT2 inhibitor users, 28,036 were taking canagliflozin, 8647 dapagliflozin, and 3186 empagliflozin.

Crude amputation rates were 10.53/10,000 person-years for new SGLT2 inhibitor users overall and 10.00/10,000 person-years for canagliflozin users, compared with 8.52/10,000 person-years for DPP-4 inhibitor users, 7.10/10,000 person-years for GLP-1 agonist users, and 4.90/10,000 person-years for combined users of the "other" oral diabetes drugs (sulfonylureas, metformin, and/or thiazolidinediones).

After propensity score matching and additional adjustments for potential confounders, there was a nonsignificant increased risk of amputation associated with new use of SGLT2 inhibitors compared with new use of DPP-4 inhibitors (adjusted hazard ratio [aHR], 1.50; 95% CI, 0.85 - 2.67) and GLP-1 agonists (aHR, 1.47; 95% CI, 0.64 - 3.36).

But compared with the "other" medications group, the amputation risk was significantly increased (aHR, 2.12).

Use of SGLT2 inhibitors was also associated with greater risks compared with the "other" drugs for vascular ulcers (aHR, 1.34), osteomyelitis (aHR, 1.44), and peripheral vascular disease (aHR, 1.11).

On the other hand, compared with new users of DPP-4 inhibitors, new users of SGLT2 inhibitors had lower risks for some outcomes, including peripheral vascular disease (aHR, 0.88) and critical limb ischemia (aHR, 0.76).

With the inclusion of patients who had prior amputations, there was a borderline significant increase in risk associated with SGLT2 inhibitor use compared with DPP-4 inhibitor use (aHR, 1.73; P = .048).

The sample size was insufficient to ascertain any difference in risk across the individual SGLT2 inhibitors, Chang and colleagues say.  

Editorialists Cite Study Flaws

Fralick and colleagues point out that the amputation rates seen in this analysis are "strikingly" lower than those seen in CANVAS, in which the study population was older and had more comorbidities. Moreover, the duration of follow-up was much longer in CANVAS, 126 weeks versus about 16 weeks in the current study.

The editorialists also note that the "new user" designation doesn't appear to have been applied to the "other" drug category, so that inclusion of more long-time users of metformin in particular may have contributed to the higher amputation risk found when new SGLT2 inhibitor users were compared with that group.

They also fault the authors for introducing potential bias by excluding insulin users, using a method of propensity matching that could have led to imprecise estimates, and not adjusting for potential confounders such as baseline use of older diabetes medications, HbA1c, or calendar time since each drug was introduced on the market.  

Chang and colleagues acknowledge the need for more data, noting, "As the regulatory communications from the FDA and European Medicines Agency make clear, there is a pressing need for further information derived from a number of sources, ranging from passive surveillance systems to meta-analyses of large studies, including observational studies of vascular outcomes such as those we examine herein."

The study was supported in part by the Johns Hopkins Center of Excellence in Regulatory Science and Innovation. Chang has reported no relevant financial relationships. Fralick was supported by the Eliot Phillipson Clinician Scientist Training Program from the University of Toronto and a PhD award from the Canadian Institutes of Health Research, neither of which were related to the topic of the manuscript.

JAMA Intern Med. Published online August 13, 2018. Abstract, Editorial

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