Amputations in Diabetes Back on the Rise, but Why?

Diabetes is by far the leading cause of nontraumatic lower-extremity amputations (LEAs). Key risk factors include poor glycemic control and loss of sensation due to peripheral neuropathy. Thus the presence or absence of LEAs can be considered an indication of the success of preventive care.

Indeed, between 1990 and 2010, when attention to tightening glycemic control and foot care grew, rates of LEAs in patients with diabetes declined precipitously throughout the world.^[1]

In a new population-based study published in Diabetes Care,^[2] however, authors reported a reversal of the declining trend such that by 2015 the reduction in rates of LEAs seen between 2000 and 2010 had been effectively eliminated.

Surprising Results, No Obvious Explanations

To conduct this study, Geiss and colleagues, from the Centers for Disease Control and Prevention (CDC), used the Nationwide Inpatient Sample, a nationally representative sample of all community-based hospitals with annual data on hospital stays. The investigators identified discharges listing diabetes as a diagnosis and which included an LEA procedure code, then calculated annual rates using population estimates from the CDC's National Health Interview Survey.

They found that age-adjusted rates of LEA per 1000 adults with diabetes decreased by 43% between 2000 and 2009, but then increased by 50% between 2009 and 2015. The increase was driven by minor amputations (foot or below), which rose 62%, and was greatest among the younger (18-44 years) and middle-aged groups (45-64 years), and among men.

The investigators noted no obvious explanations for these results. They speculated that early preventive practices may be suboptimal or that treatment of foot ulcers is delayed.

Another, more positive possibility is that the rise in minor amputations indicates more aggressive, early amputation to avoid loss of more of the limb. Whatever the reason(s), there is a clear need to understand why this apparently discouraging trend has emerged.

Are New Treatments Causing This Reversal?

Concern about LEAs as a complication of diabetes grew after the CANVAS study reported a near doubling of LEAs—primarily of the toe or midfoot—with treatment with a sodium-glucose cotransporter 2 (SGLT2) inhibitor.^[3] Since then, subsequent observational studies using large databases have produced mixed results.

Ryan and colleagues^[4] found no difference in below-the-knee amputations when comparing new users of canagliflozin, other SGLT2 inhibitors, and non-SGLT2 inhibitor drugs. Chang and colleagues,^[5] however, found a doubling of risk with SGLT2 inhibitors vs a combination group of older drugs (metformin, sulfonylurea, glitazone), and Ueda and colleagues^[6] reported a doubling of risk for patients taking SGLT2 inhibitors compared with those taking glucagon-like peptide 1 receptor agonists (GLP-1s).

In all of these studies, amputation rates were low and follow-up was short. It should also be noted that there is no known mechanism of action with SGLT2 inhibitors that would increase risk for LEAs.

Nevertheless, the association cannot yet be ruled out. Longer-term studies are needed. In the meantime, the apparent cardiovascular benefits of SGLT2 inhibitors almost certainly outweigh the low risk for LEAs, although treatment decisions should always be based on an individual patient's risk-factor profile.

Or Have Clinicians Gone Soft on A1c Targets?

Despite the timing, the alarming rise in LEAs reported by Geiss and colleagues cannot possibly be explained by the use of SGLT2 inhibitors. Even if the possible doubling of LEA risk is real, it is the doubling of a small absolute number, and there are not nearly enough users of SGLT2 inhibitors to account for the resurgence in LEAs.

A potentially more troubling possibility is that the rise in LEA rates began shortly after the 2008 results of ACCORD,^[7] in which intensive glycemic control appeared to increase the risk for mortality. It is possible that clinicians subsequently softened their views on glycemic targets.

Although the American Diabetes Association (ADA) guidelines have continued to recommend an A1c target of less than 7% for most patients, the 2012 Position Statement^[8] acknowledged that the 7% target is not for everyone, thus introducing some wiggle room for intensity of treatment for some patients, and potentially reinforcing a misinterpreted message from ACCORD that glycemic control is not as important as once thought.

To be clear, current guidelines continue to recommend a target A1c of < 7% as a "reasonable goal," with a less stringent goal for patients with limited life expectancy, advanced complications, extensive comorbidities, or long-standing diabetes.^[9]

A Simple Solution: Checking the Feet

Whatever the reason for the disturbing trend in LEAs, this is clearly a situation that we do not want to continue. SGLT2 inhibitors are here to stay; indeed, the ADA now recommends them for patients with diabetes who have atherosclerotic heart disease, especially those who have or are at high risk for heart failure, or chronic kidney disease.^[10]

Regardless of the use of SGLT2 inhibitors, a quick look at a patient's feet at (nearly) every visit does not seem to be too much to ask. Current guidelines suggest a comprehensive foot exam annually for all patients, and inspection at every visit only for those with evidence of sensory loss, previous ulceration, or amputation.^[11] However, inspection at every visit is something that could be done quickly by a nurse or a medical assistant.

Even though LEAs remain relatively rare, their debilitating effects warrant a little extra effort, which may be the best way to halt their resurgence. Furthermore, patients should be educated and re-educated about the risk for LEA, and to be on the lookout for signs of peripheral neuropathy or skin damage that could become or has ulcerated. Unfortunately, patients with diabetes need tenacious, ongoing attention to minimize LEAs and other complications.

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