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Diabetes Watch

Do SGLT-2 Inhibitors Increase The Risk Of Amputation?

Multiple studies link sodium-glucose cotransporter 2 (SGLT-2) inhibitors, the newest class of medications for treating diabetes, with a possible increase in lower extremity amputations.1-8 The exact cause is unknown and the research is conflicting.­6

In 2013, the Food and Drug Administration (FDA) approved the first SGLT-2 inhibitor, canagliflozin (Invokana®, Janssen Pharmaceuticals), for the treatment of type 2 diabetes. More recently, the FDA approved two new SGLT-2 inhibitors, dapagliflozin (Farxiga®, AstraZeneca) and empagliflozin (Jardiance®, Lilly). 

SGLT-2 inhibitors are unique in that they inhibit the reabsorption of glucose in the kidneys unlike other diabetic medications.5 The chemical starting point for SGLT-2 inhibitors is phlorizin, a natural product derived from apple tree bark, which was first reported on in 1835.5 Phlorizin induces glucosuria by inhibiting renal tubular glucose reabsorption. In its natural state, phlorizin wanes over several hours, necessitating multiple large doses throughout the day, thus making it impractical for pharmaceutical use. However, modifying the phlorizin scaffold and extending the half-life made the medication viable for practical medicinal use. Newly formulated SLGT-2 inhibitors achieve maximal concentrations in one to 1.5 hours after a single oral dose and have a terminal half-life between eight and 16 hours.5

In addition to treating diabetes, this class of medication also reportedly decreases the risk of major cardiovascular events and slows the progression of diabetic kidney disease.5 SGLT-2 inhibitors additionally increase insulin sensitivity and enhance glucose-stimulated insulin secretion by alleviating glucotoxicity.5 There is further evidence of weight loss promotion, which can lead to overall metabolic improvement.5

Unfortunately, SGLT-2 inhibitors also have many potential adverse drug reactions. Some of the side effects are potentially life-threatening. The reactions are mostly mechanism-based and were not recognized until after the medications had received FDA approval.5 The potential adverse reactions include genitourinary and perineal infections (Fournier gangrene), hypoglycemia with concomitant use of insulin, ketoacidosis, hypotension, acute kidney injury, bone fracture and lower extremity amputations.

What The Literature Reveals 

In 2016, data from the randomized controlled trial CANVAS (Canagliflozin Cardiovascular Assessment Study) showed a significant increased rate of lower extremity amputations (6.3 versus 3.4 per 1,000 patient-years) in patients treated with canagliflozin in comparison to those treated with a placebo.1 Most of the patients who underwent amputation already had a history of amputation or peripheral vascular disease. The amputations included toe, midfoot, below-knee and above-knee amputation. The most frequent amputations were at the toe and midfoot levels. An increased risk of amputation began to emerge after six to 12 months of taking canaglifozin. After the results were published, both the FDA and European Medicines Agency issued warnings about amputation risks associated with SGLT-2 inhibitors.6-8

In 2018, the OBSERVE 4-D study, a meta-analysis of four observational databases of patients with type 2 diabetes, was published.2 The analysis compared 142,800 new users of canagliflozin, 110,897 new users of other SGLT-2 inhibitors and 460,885 new users of other diabetes medications. These researchers found no increased amputation risk for patients taking the SGLT-2 inhibitors.

However, there was one point of weakness of the analysis. In comparison with the CANVAS Program, OBSERVE 4-D had a shorter follow-up time (60 to 100 days versus 126 weeks). Therefore, OBSERVE 4-D had limited statistical power to detect differences in the six- to 12-month period. It was during this time in which amputation risk began to emerge in the CANVAS study, particularly in patients with established cardiovascular disease. 

Another study by Chang and colleagues evaluated real-world data concerning SGLT-2 and amputations.3 The 2018 retrospective population-based cohort study focused on two million commercially insured patients and used propensity score weighting to balance baseline differences among groups. The researchers found that after score weighting and adjusting for demographics, comorbidities, severity of diabetes and medications, there was a non-statistically significant increased risk for amputation in those taking SGLT-2 inhibitors in comparison with DPP-4 inhibitors and GLP-1 receptor agonists. In addition, there was a statistically significant increase in amputations in the SGLT-2 inhibitor group in comparison to patients taking sulfonylureas, metformin or thiazolidinediones. 

This study also had limitations.3 The data set consisted of privately insured patients so comparison to other populations may be questionable. The duration of follow-up was limited and the event rates were low overall. The sample sizes were insufficient to examine for evidence of heterogeneity of effects across the different SLGT-2 inhibitor medications. There was also concern about a higher use of statin use among patients taking the SGLT-2 inhibitors, which may have attenuated risk estimates as statins may be protective against amputations. The authors concluded that further studies were necessary.

Most recently, a cohort study conducted with data from the health and administrative registers in Sweden and Denmark assessed the association between the use of SGLT-2 inhibitors and lower limb amputation, bone fracture, diabetic ketoacidosis, acute kidney injury, serious urinary tract infection, venous thromboembolism, and acute pancreatitis.4 They found that the use of SLGT-2 inhibitors had double the risk for lower limb amputation (2.7 events versus 1.1 events per 1,000 patient years) in comparison to GLP-1 receptor agonists. This increased risk mirrors the findings in the CANVAS program. In contrast to the CANVAS program, this study found the risk of amputation was consistent in patients with and without cardiovascular disease, patients with and without peripheral arterial disease, or patients with previous amputation.1,4 They did find, however, that the event rates for amputation were higher in the subgroups with such history. 

The exact mechanisms that may increase amputation risk with SGLT-2 use are still unknown. There is speculation that there may be a connection between the promotion of extracellular fluid volume depletion and glucosuria with subsequent hemoconcentration in patients with diabetes who are already at risk.3 An exploratory analysis by the European Medicines Agency found that those with the highest risk are patients with chronic kidney disease.3 However, there is no definitive evidence at this time. 

Concluding Thoughts

Given the disparity between the various studies, it remains uncertain whether SGLT-2 inhibitors are associated with an increased risk of foot and leg amputations in comparison to placebo. However, because the use of SGLT-2 inhibitors is associated with a statistically significant increase in amputations in comparison to three older diabetes medications, further testing is necessary as the rate of SGLT-2 inhibitor prescriptions will continue to rise and potentially outpace the older medications, possibly placing more patients at a higher risk of amputation over time.3

Given that the data is not definitive regarding the association between SLGT-2 inhibitors and lower extremity amputation, clinicians need to weigh the potential risks of the medications against their benefits and alternatives. Both the FDA and European Medicines Agency have advised that there is a need for further research into this topic.7,8 

Dr. Swain is a board-certified wound specialist physician (CWSP) of the American Board of Wound Management, and a Diplomate of the American Board of Podiatric Medicine. He is the Medical Director of the St. Vincent’s Wound Care and Hyperbaric Center at St. Vincent’s Southside Hospital in Jacksonville, Fla., and is in private practice at the First Coast Cardiovascular Institute in Jacksonville, Fla.

Diabetes Watch
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By David Swain, DPM
References

1. Neal B, Perkovic V, Mahaffey K, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. New Eng J Med. 2017;377(7):644-657.

2. Ryan PB, Buse JB, Schuemie MJ, et al. Comparative effectiveness of canagliflozin, SGLT2 inhibitors, and non-SGLT2 inhibitors on the risk of hospitalization for heart failure and amputation in patients with type 2 diabetes mellitus: A real-world meta-analysis of 4 observational databases (OBSERVE-4D). Diabetes Obes Metab. 2018;20(11):2585-2597.

3. Chang H, Singh S, Mansour O, Baksh S, Alexander GC. Association between sodium-glucose cotransporter 2 inhibitors and lower extremity amputation among patients with type 2 diabetes. JAMA Intern Med. 2018;178(9):1190-1198.

4. Ueda P, Svanström H, Melbye M, et al. Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study. BMJ. 2018;363:k4365.

5. Beitelshees AL, Leslie BR, Taylor SI. Sodium-glucose cotransporter 2 inhibitors: A case study in translational research. Diabetes. 2019; 68(6):1109-1120.

6. George J. The SGLT-2 inhibitor-amputation link: why is there conflicting data? Medpage Today. Available at: https://www.medpagetoday.com/reading-room/endocrine-society/diabetes/76711 . Accessed November 26, 2019.

7. FDA Drug Safety Communication: Interim clinical trial results find increased risk of leg and foot amputations, mostly affecting the toes, with the diabetes medicine canagliflozin (Invokana, Invokamet); FDA to investigate.  Available at:  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-interim-clinical-trial-results-find-increased-risk-leg-and-foot . Accessed December 15, 2019.

8. PRAC concludes that diabetes medicine canagliflozin may contribute to risk of toe amputation. Available at: https://www.ema.europa.eu/en/documents/referral/sglt2-inhibitors-previously-canagliflozin-article-20-procedure-prac-concludes-diabetes-medicine_en.pdf . Accessed December 15, 2019.

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